Organophosphate derivatives

ABSTRACT

Provided herein are organophosphates and pharmaceutical compositions comprising said compounds.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a § 371 U.S. National Stage Application ofInternational Application No. PCT/US2018/044389, filed Jul. 30, 2018,which claims benefit of U.S. Provisional Application No. 62/538,879,filed on Jul. 31, 2017, and U.S. Provisional Application No. 62/637,960,filed on Mar. 2, 2018, each of which is herein incorporated by referencein its entirety.

BACKGROUND

Cancer is among the leading causes of death worldwide. The number of newcancer cases is expected to rise to 22 million within the next twodecades. Improved therapies are needed to treat this increasing patientpopulation.

BRIEF SUMMARY OF THE INVENTION

This disclosure provides, for example, organophosphate compounds, theiruse as medicinal agents for the treatment of cancer, processes for theirpreparation, and pharmaceutical compositions that include disclosedcompounds as at least one active ingredient. The disclosure alsoprovides for the use of compounds described herein as medicaments and/orin the manufacture of medicaments for the treatment of cancer.

In one aspect is a compound of Formula (I):

wherein:

-   -   R¹ is

-   -   R² is —C(O)R⁸;    -   R³ is H, —C(O)R⁹, or —C(O)OR⁹;    -   R⁴ is H;    -   R⁵ is H, C₃₋₂₂alkyl, C₃₋₂₂alkenyl, C₃₋₂₂alkynyl, C₃₋₂₂haloalkyl,        —C₁₋₆alkyl-OC(O)C₁₋₂₂alkyl, C₃₋₈cycloalkyl, C₆₋₁₀aryl,        —C₁₋₈alkyl-C₆₋₁₀aryl, C₂₋₉heteroaryl, or        —C₁₋₈alkyl-C₂₋₉heteroaryl, wherein C₆₋₁₀aryl,        —C₁₋₈alkyl-C₆₋₁₀aryl, C₂₋₉heteroaryl, or        —C₁₋₈alkyl-C₂₋₉heteroaryl are optionally substituted with 1, 2,        3, or 4 R¹⁴;    -   R⁶ is C₃₋₂₂alkyl, C₃₋₂₂alkenyl, C₃₋₂₂alkynyl, C₃₋₂₂haloalkyl,        —C₁₋₆alkyl-OC(O)C₁₋₂₂alkyl, C₃₋₈cycloalkyl, C₆₋₁₀aryl,        —C₁₋₈alkyl-C₆₋₁₀aryl, C₂₋₉heteroaryl, or        —C₁₋₈alkyl-C₂₋₉heteroaryl, wherein C₆₋₁₀aryl,        —C₁₋₈alkyl-C₆₋₁₀aryl C₂₋₉heteroaryl, or        —C₁₋₈alkyl-C₂₋₉heteroaryl are optionally substituted with 1, 2,        3, or 4 R¹⁴;    -   each R⁷ is independently selected from halogen, C₁₋₈alkyl,        C₁₋₈haloalkyl, and C₁₋₈alkoxy;    -   R⁸ is C₃₋₂₂alkyl, C₃₋₂₂alkenyl, C₃₋₂₂alkynyl, C₃₋₂₂haloalkyl,        C₃₋₈cycloalkyl, C₆₋₁₀aryl, —C₁₋₈alkyl-C₆₋₁₀aryl C₂₋₉heteroaryl,        or —C₁₋₈alkyl-C₂₋₉heteroaryl, wherein C₆₋₁₀aryl,        —C₁₋₈alkyl-C₆₋₁₀aryl, C₂₋₉heteroaryl, or        —C₁₋₈alkyl-C₂₋₉heteroaryl are optionally substituted with 1, 2,        3, or 4 R¹⁴;    -   R⁹ is C₁₋₁₂alkyl;    -   R¹⁰ and R¹¹ are each independently H or C₁₋₁₂alkyl; or R¹⁰ and        R¹¹ form a 5- or 6-membered cycloalkyl ring or a 5- or        6-membered heterocycloalkyl ring, wherein the 5- or 6-membered        cycloalkyl ring or the 5- or 6-membered heterocycloalkyl ring        are optionally substituted with one or two R¹³;    -   R¹² is H or C₁₋₁₂alkyl;    -   each R¹³ is independently selected from C₁₋₁₂alkyl;    -   each R¹⁴ is independently selected from halogen, C₁₋₈alkyl        C₁₋₈haloalkyl C₁₋₈alkoxy, and —C(O)R¹³;    -   m is 0 or 1;    -   n is 0, 1, 2, 3, or 4; and    -   p is 0 or 1;    -   or a pharmaceutically acceptable salt thereof.

In another aspect is a compound of Formula (I′):

wherein:

-   -   R¹ is

-   -   R² is —C(O)R⁸;    -   R³ is H, —C(O)R⁹, or —C(O)OR⁹;    -   R⁴ is H;    -   R⁵ is H, C₃₋₂₂alkyl, C₃₋₂₂alkenyl, C₃₋₂₂alkynyl, C₃₋₂₂haloalkyl,        —C₁₋₄alkyl-OC(O)C₁₋₈alkyl, C₃₋₈cycloalkyl, C₆₋₁₀aryl,        —C₁₋₈alkyl-C₆₋₁₀aryl, C₂₋₉heteroaryl, or        —C₁₋₈alkyl-C₂₋₉heteroaryl, wherein C₆₋₁₀aryl,        —C₁₋₈alkyl-C₆₋₁₀aryl, C₂₋₉heteroaryl, or        —C₁₋₈alkyl-C₂₋₉heteroaryl are optionally substituted with 1, 2,        3, or 4 R¹⁴;    -   R⁶ is C₃₋₂₂alkyl, C₃₋₂₂alkenyl, C₃₋₂₂alkynyl, C₃₋₂₂haloalkyl,        —C₁₋₄alkyl-OC(O)C₁₋₈alkyl, C₃₋₈cycloalkyl, C₆₋₁₀aryl,        —C₁₋₈alkyl-C₆₋₁₀aryl C₂₋₉heteroaryl, or        —C₁₋₈alkyl-C₂₋₉heteroaryl, wherein C₆₋₁₀aryl,        —C₁₋₈alkyl-C₆₋₁₀aryl, C₂₋₉heteroaryl, or        —C₁₋₈alkyl-C₂₋₉heteroaryl are optionally substituted with 1, 2,        3, or 4 R¹⁴;    -   each R⁷ is independently selected from halogen, C₁₋₈alkyl,        C₁₋₈haloalkyl, and C₁₋₈alkoxy;    -   R⁸ is C₃₋₂₂alkyl, C₃₋₂₂alkenyl, C₃₋₂₂alkynyl, C₃₋₂₂haloalkyl,        C₃₋₈cycloalkyl, C₆₋₁₀aryl, —C₁₋₈alkyl-C₆₋₁₀aryl, C₂₋₉heteroaryl,        or —C₁₋₈alkyl-C₂₋₉heteroaryl, wherein C₆₋₁₀aryl,        —C₁₋₈alkyl-C₆₋₁₀aryl C₂₋₉heteroaryl, or        —C₁₋₈alkyl-C₂₋₉heteroaryl are optionally substituted with 1, 2,        3, or 4 R¹⁴;    -   R⁹ is C₁₋₁₂alkyl;    -   R¹⁰ and R¹¹ are each independently H or C₁₋₁₂alkyl; or R¹⁰ and        R¹¹ form a 5- or 6-membered cycloalkyl ring or a 5- or        6-membered heterocycloalkyl ring, wherein the 5- or 6-membered        cycloalkyl ring or the 5- or 6-membered heterocycloalkyl ring        are optionally substituted with one or two R¹³;    -   R¹² is H or C₁₋₁₂alkyl;    -   each R¹³ is independently selected from C₁₋₁₂alkyl;    -   each R¹⁴ is independently selected from halogen, C₁₋₈alkyl,        C₁₋₈haloalkyl, C₁₋₈alkoxy, and —C(O)R¹³;    -   m is 0 or 1;    -   n is 0, 1, 2, 3, or 4; and    -   p is 0 or 1;    -   or a pharmaceutically acceptable salt thereof.

In another embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R¹ is

In another embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R⁵ is C₃₋₁₆alkyl. Inanother embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R⁵ is C₃₋₁₂alkyl. Inanother embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R⁵ is C₆₋₁₄alkyl. Inanother embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R⁵ is C₆₋₁₀alkyl. Inanother embodiment is a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, wherein R⁵ is —C₁₋₄alkyl-OC(O)C₁₋₁₆alkyl. Inanother embodiment is a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, wherein R⁵ is —C₁₋₄alkyl-OC(O)C₁₋₁₂alkyl. Inanother embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R⁵ is—C₁₋₄alkyl-OC(O)C₁₋₈alkyl. In another embodiment is a compound ofFormula (I) or (I′), or a pharmaceutically acceptable salt thereof,wherein R⁵ is —C₁₋₂alkyl-OC(O)C₁₋₆alkyl. In another embodiment is acompound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R⁵ is —CH₂—OC(O)C(CH₃)₃. In another embodiment is acompound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R⁵ is H. In another embodiment is a compound of Formula(I) or (I′), or a pharmaceutically acceptable salt thereof, wherein R⁶is C₃₋₁₆alkyl. In another embodiment is a compound of Formula (I) or(I′), or a pharmaceutically acceptable salt thereof, wherein R⁶ isC₃₋₁₂alkyl. In another embodiment is a compound of Formula (I) or (I′),or a pharmaceutically acceptable salt thereof, wherein R⁶ is C₆₋₁₀alkyl.In another embodiment is a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein R⁶ is—C₁₋₄alkyl-OC(O)C₁₋₁₆alkyl. In another embodiment is a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein R⁶is —C₁₋₄alkyl-OC(O)C₁₋₁₂alkyl. In another embodiment is a compound ofFormula (I) or (I′), or a pharmaceutically acceptable salt thereof,wherein R⁶ is —C₁₋₄alkyl-OC(O)C₁₋₈alkyl. In another embodiment is acompound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R⁶ is —C₁₋₂alkyl-OC(O)C₁₋₆alkyl. In another embodimentis a compound of Formula (I) or (I′), or a pharmaceutically acceptablesalt thereof, wherein R⁶ is —CH₂—OC(O)C(CH₃)₃. In another embodiment isa compound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R¹ is

In another embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein m is 0. In anotherembodiment is a compound of Formula (I) or (I′), or a pharmaceuticallyacceptable salt thereof, wherein m is 1. In another embodiment is acompound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R¹⁰ is H. In another embodiment is a compound ofFormula (I) or (I′), or a pharmaceutically acceptable salt thereof,wherein R¹⁰ is C₁₋₁₂alkyl. In another embodiment is a compound ofFormula (I) or (I′), or a pharmaceutically acceptable salt thereof,wherein R¹¹ is H. In another embodiment is a compound of Formula (I) or(I′), or a pharmaceutically acceptable salt thereof, wherein R¹⁰ and R¹¹form a 5- or 6-membered cycloalkyl ring or a 5- or 6-memberedheterocycloalkyl ring, wherein the 5- or 6-membered cycloalkyl ring orthe 5- or 6-membered heterocycloalkyl ring are optionally substitutedwith one or two R¹³. In another embodiment is a compound of Formula (I)or (I′), or a pharmaceutically acceptable salt thereof, wherein R¹ is

In another embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein each R⁷ isindependently selected from C₁₋₈alkyl, C₁₋₈haloalkyl, and C₁₋₈alkoxy. Inanother embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein each R⁷ isindependently selected from C₁₋₈alkyl. In another embodiment is acompound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein n is 1 or 2. In another embodiment is a compound ofFormula (I) or (I′), or a pharmaceutically acceptable salt thereof,wherein n is 0. In another embodiment is a compound of Formula (I) or(I′), or a pharmaceutically acceptable salt thereof, wherein p is 0. Inanother embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein p is 1. In anotherembodiment is a compound of Formula (I) or (I′), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₃₋₁₅alkyl. In another embodimentis a compound of Formula (I) or (I′), or a pharmaceutically acceptablesalt thereof, wherein R⁸ is C₆₋₁₈alkyl. In another embodiment is acompound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R⁸ is C₆₋₁₂alkyl. In another embodiment is a compoundof Formula (I) or (I′), or a pharmaceutically acceptable salt thereof,wherein R⁸ is —(CH₂)₇CH₂.

In another aspect is a compound of Formula (II):

wherein:

-   -   R³ is H, H, —C(O)R⁹, or —C(O)OR⁹;    -   R⁴ is H;    -   R⁹ is C₁₋₈alkyl;    -   R¹¹ is C₃₋₂₂alkyl, C₃₋₂₂alkenyl, C₃₋₂₂alkynyl, C₃₋₂₂haloalkyl,        —C₁₋₄alkyl-OC(O)C₁₋₈alkyl, C₆₋₁₀aryl, —C₁₋₈alkyl-C₆₋₁₀aryl,        C₂₋₉heteroaryl, or —C₁₋₈alkyl-C₂₋₉heteroaryl, wherein C₆₋₁₀aryl,        —C₁₋₈alkyl-C₆₋₁₀aryl, C₂₋₉heteroaryl, or        —C₁₋₈alkyl-C₂₋₉heteroaryl are optionally substituted with 1, 2,        3, or 4 R¹²;    -   each R¹² is independently selected from halogen, C₁₋₈alkyl,        C₁₋₈haloalkyl, C₁₋₈alkoxy, and —C(O)R¹³; and    -   each R¹³ is independently selected from C₁₋₁₂alkyl;    -   or a pharmaceutically acceptable salt thereof.

In another embodiment is a compound of Formula (II), or apharmaceutically acceptable salt thereof, wherein R¹¹ is C₃₋₁₅alkyl. Inanother embodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is C₆₋₁₂alkyl. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is C₈₋₁₀alkyl. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is C₈₋₂₂alkyl. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is C₁₆₋₂₂alkyl. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is —C₁₋₄alkyl-OC(O)C₁₋₈alkyl. Inanother embodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is —C₁₋₂alkyl-OC(O)C₁₋₆alkyl. Inanother embodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is —CH₂—OC(O)C(CH₃)₃. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is C₆₋₁₀aryl optionally substitutedwith 1, 2, 3, or 4 R¹². In another embodiment is a compound of Formula(II), or a pharmaceutically acceptable salt thereof, wherein R¹¹ isphenyl optionally substituted with 1, 2, or 3 R¹². In another embodimentis a compound of Formula (II), or a pharmaceutically acceptable saltthereof, wherein R¹¹ is phenyl optionally substituted with 1, 2, or 3R¹² and each R¹² is independently selected from C₁₋₈alkyl, C₁₋₈alkoxy,and —C(O)R¹³. In another embodiment is a compound of Formula (II), or apharmaceutically acceptable salt thereof, wherein R¹¹ is phenyloptionally substituted with 1 or 2 R¹² and each R¹² is independentlyselected from C₁₋₈alkyl and C₁₋₈alkoxy. In another embodiment is acompound of Formula (II), or a pharmaceutically acceptable salt thereof,wherein R¹¹ is —C₁₋₈alkyl-C₆₋₁₀aryl optionally substituted with 1, 2, 3,or 4 R¹². In another embodiment is a compound of Formula (II), or apharmaceutically acceptable salt thereof, wherein R¹¹ is —CH₂-phenyloptionally substituted with 1, 2, or 3 R¹². In another embodiment is acompound of Formula (II), or a pharmaceutically acceptable salt thereof,wherein R¹¹ is —CH₂-phenyl optionally substituted with 1, 2, or 3 R¹²and each R¹² is independently selected from C₁₋₈alkyl, C₁₋₈alkoxy, and—C(O)R¹³. In another embodiment is a compound of Formula (II), or apharmaceutically acceptable salt thereof, wherein R¹¹ is —CH₂-phenyloptionally substituted with 1, 2, or 3 R¹² and each R¹² is independentlyselected from C₁₋₈alkyl and C₁₋₈alkoxy. In another embodiment is acompound of Formula (I), (I′), or (II), or a pharmaceutically acceptablesalt thereof, wherein R³ is H. In another embodiment is a compound ofFormula (I), (I′), or (II), or a pharmaceutically acceptable saltthereof, wherein R³ is —C(O)R⁹. In another embodiment is a compound ofFormula (I), (I′), or (II), or a pharmaceutically acceptable saltthereof, wherein R³ is —C(O)OR⁹.

In another embodiment is a pharmaceutical composition comprising acompound of Formula (I), (I′), or (II) described herein, or apharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable excipient.

In another embodiment is a method of treating cancer in a patient,comprising administering to the patient in need thereof atherapeutically effective amount of a compound of Formula (I), (I′), or(II) described herein, or a pharmaceutically acceptable salt thereof. Inanother embodiment is a method of treating an infectious disease in apatient, comprising administering to the patient in need thereof atherapeutically effective amount of a compound of Formula (I), (I′), or(II) described herein, or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

Nucleoside analogues constitute a major class of chemotherapeutic agentsand are used for the treatment of patients with cancer. This group ofagents, known as antimetabolites, includes a variety of pyrimidine andpurine nucleoside derivatives with cytotoxic activity in bothhematological and solid tumors. Gemcitabine(2′,2′-difluoro-2′-deoxycytidine) is a pyrimidine nucleoside analogue,shown to be active against several solid tumor types.

Both innate and acquired resistance to nucleoside analogues is a problemin the treatment of cancer and is regarded as a driver of poor patientsurvival outcomes. Gemcitabine faces inherent and acquired cancerresistance mechanisms that limit its effectiveness. These include (i)poor conversion of gemcitabine into the active forms, dFdCDP and dFdCTP;(ii) rapid degradation into toxic byproducts; and (iii) limited uptakeby cancer cells. These effects are due to the following: (i)down-regulation of the key initial phosphorylating enzyme deoxycytidinekinase (dCK) required to convert gemcitabine into the monophosphateform; (ii) expression of the key deactivating enzyme cytidine deaminase;and (iii) deficiency of nucleoside transporter proteins. In addition,increased expression and/or activity of cytidine deaminase (CDA)increases the degradation of gemcitabine into the toxic metabolite2′,2′-difluoro-2′-deoxyuridine (dFdU). Because of these processes,single agent gemcitabine has limited activity in cancer treatment.

As used herein and in the appended claims, the singular forms “a,”“and,” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “an agent” includesa plurality of such agents, and reference to “the cell” includesreference to one or more cells (or to a plurality of cells) andequivalents thereof. When ranges are used herein for physicalproperties, such as molecular weight, or chemical properties, such aschemical formulae, all combinations and subcombinations of ranges andspecific embodiments therein are intended to be included. The term“about” when referring to a number or a numerical range means that thenumber or numerical range referred to is an approximation withinexperimental variability (or within statistical experimental error), andthus the number or numerical range varies between 1% and 15% of thestated number or numerical range. The term “comprising” (and relatedterms such as “comprise” or “comprises” or “having” or “including”) isnot intended to exclude that which in other certain embodiments, forexample, an embodiment of any composition of matter, composition,method, or process, or the like, described herein, may “consist of” or“consist essentially of” the described features.

Definitions

As used in the specification and appended claims, unless specified tothe contrary, the following terms have the meaning indicated below.

As used herein, C₁-C_(x) includes C₁-C₂, C₁-C₃ . . . C₁-C_(x). C₁-C_(x)refers to the number of carbon atoms that make up the moiety to which itdesignates (excluding optional substituents).

“Amino” refers to the —NH₂ radical.

“Cyano” refers to the —CN radical.

“Nitro” refers to the —NO₂ radical.

“Oxa” refers to the —O— radical.

“Oxo” refers to the ═O radical.

“Thioxo” refers to the ═S radical.

“Imino” refers to the ═N—H radical.

“Oximo” refers to the ═N—OH radical.

“Alkyl” or “alkylene” refers to a straight or branched hydrocarbon chainradical consisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to eighteen carbon atoms (e.g., C₁-C₁₈alkyl). In certain embodiments, an alkyl comprises three to eighteencarbon atoms (e.g., C₃-C₁₈ alkyl). In certain embodiments, an alkylcomprises one to fifteen carbon atoms (e.g., C₁-C₁₅ alkyl). In certainembodiments, an alkyl comprises one to twelve carbon atoms (e.g., C₁-C₁₂alkyl). In certain embodiments, an alkyl comprises one to eight carbonatoms (e.g., C₁-C₈ alkyl). In other embodiments, an alkyl comprises oneto six carbon atoms (e.g., C₁-C₆ alkyl). In other embodiments, an alkylcomprises one to five carbon atoms (e.g., C₁-C₅ alkyl). In otherembodiments, an alkyl comprises one to four carbon atoms (e.g., C₁-C₄alkyl). In other embodiments, an alkyl comprises one to three carbonatoms (e.g., C₁-C₃ alkyl). In other embodiments, an alkyl comprises oneto two carbon atoms (e.g., C₁-C₂ alkyl). In other embodiments, an alkylcomprises one carbon atom (e.g., C₁ alkyl). In other embodiments, analkyl comprises five to fifteen carbon atoms (e.g., C₅-C₁₅ alkyl). Inother embodiments, an alkyl comprises five to eight carbon atoms (e.g.,C₅-C₈ alkyl). In other embodiments, an alkyl comprises two to fivecarbon atoms (e.g., C₂-C₅ alkyl). In other embodiments, an alkylcomprises three to five carbon atoms (e.g., C₃-C₅ alkyl). In otherembodiments, the alkyl group is selected from methyl, ethyl, 1-propyl(n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl),1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl),1,1-dimethylethyl (tert-butyl), and 1-pentyl (n-pentyl). The alkyl isattached to the rest of the molecule by a single bond. Unless statedotherwise specifically in the specification, an alkyl group isoptionally substituted by one or more of the following substituents:halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl,—OR^(a), —SR^(a), —OC(O)—R^(f), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(f), —OC(O)—NR^(a)R^(f),—N(R^(a))C(O)R^(f), —N(R^(a))S(O)_(t)R^(f) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(f) (where t is 1 or 2)and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl,heterocycloalkyl, heteroaryl, or heteroarylalkyl, and each R^(f) isindependently alkyl, haloalkyl, cycloalkyl, aryl, aralkyl,heterocycloalkyl, heteroaryl, or heteroarylalkyl.

“Alkoxy” refers to a radical bonded through an oxygen atom of theformula —O-alkyl, where alkyl is an alkyl chain as defined above.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one carbon-carbon double bond, and having from two to eighteencarbon atoms. In certain embodiments, an alkenyl comprises three toeighteen carbon atoms. In certain embodiments, an alkenyl comprisesthree to twelve carbon atoms. In certain embodiments, an alkenylcomprises six to twelve carbon atoms. In certain embodiments, an alkenylcomprises six to ten carbon atoms. In certain embodiments, an alkenylcomprises eight to ten carbon atoms. In certain embodiments, an alkenylcomprises two to eight carbon atoms. In other embodiments, an alkenylcomprises two to four carbon atoms. The alkenyl is attached to the restof the molecule by a single bond, for example, ethenyl (i.e., vinyl),prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl,and the like. Unless stated otherwise specifically in the specification,an alkenyl group is optionally substituted by one or more of thefollowing substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(f), —N(R^(a))₂,—C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(f),—OC(O)—NR^(a)R^(f), —N(R^(a))C(O)R^(f), —N(R^(a))S(O)_(t)R^(f) (where tis 1 or 2), —S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(f) (where tis 1 or 2) and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a)is independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl,heterocycloalkyl, heteroaryl, or heteroarylalkyl, and each R^(f) isindependently alkyl, haloalkyl, cycloalkyl, aryl, aralkyl,heterocycloalkyl, heteroaryl, or heteroarylalkyl.

“Alkynyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one carbon-carbon triple bond, having from two to eighteen carbonatoms. In certain embodiments, an alkynyl comprises three to eighteencarbon atoms. In certain embodiments, an alkynyl comprises three totwelve carbon atoms. In certain embodiments, an alkynyl comprises six totwelve carbon atoms. In certain embodiments, an alkynyl comprises six toten carbon atoms. In certain embodiments, an alkynyl comprises eight toten carbon atoms. In certain embodiments, an alkynyl comprises two toeight carbon atoms. In other embodiments, an alkynyl has two to fourcarbon atoms. The alkynyl is attached to the rest of the molecule by asingle bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl,and the like. Unless stated otherwise specifically in the specification,an alkynyl group is optionally substituted by one or more of thefollowing substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(f), —N(R^(a))₂,—C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(f),—OC(O)—NR^(a)R^(f), —N(R^(a))C(O)R^(f), —N(R^(a))S(O)_(t)R^(f) (where tis 1 or 2), —S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(f) (where tis 1 or 2) and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a)is independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl,heterocycloalkyl, heteroaryl, or heteroarylalkyl, and each R^(f) isindependently alkyl, haloalkyl, cycloalkyl, aryl, aralkyl,heterocycloalkyl, heteroaryl, or heteroarylalkyl.

“Aryl” refers to a radical derived from an aromatic monocyclic ormulticyclic hydrocarbon ring system by removing a hydrogen atom from aring carbon atom. The aromatic monocyclic or multicyclic hydrocarbonring system contains only hydrogen and carbon from six to eighteencarbon atoms, where at least one of the rings in the ring system isfully unsaturated, i.e., it contains a cyclic, delocalized (4n+2)π-electron system in accordance with the Hückel theory. The ring systemfrom which aryl groups are derived include, but are not limited to,groups such as benzene, fluorene, indane, indene, tetralin andnaphthalene. Unless stated otherwise specifically in the specification,the term “aryl” or the prefix “ar-” (such as in “aralkyl”) is meant toinclude aryl radicals optionally substituted by one or more substituentsselected from alkyl, alkenyl, alkynyl, halo, haloalkyl, cyano, nitro,aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl,heteroaryl, heteroarylalkyl, —R^(b)—OR^(a), —R^(b)—OC(O)—R^(a),—R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂,—R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂,—R^(b)—O—R^(c)—C(O)N(R^(a))₂, —R^(b)—N(R^(a))C(O)OR^(a),—R^(b)—N(R^(a))C(O)R^(a), —R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(a)(where t is 1 or 2), and —R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2),where each R^(a) is independently hydrogen, alkyl, haloalkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl,heteroaryl, or heteroarylalkyl, each R^(b) is independently a directbond or a straight or branched alkylene or alkenylene chain, and R^(c)is a straight or branched alkylene or alkenylene chain.

“Aryloxy” refers to a radical bonded through an oxygen atom of theformula —O-aryl, where aryl is as defined above.

“Aralkyl” refers to a radical of the formula —R^(c)-aryl where R^(c) isan alkylene chain as defined above, for example, methylene, ethylene,and the like. The alkylene chain part of the aralkyl radical isoptionally substituted as described above for an alkylene chain. Thearyl part of the aralkyl radical is optionally substituted as describedabove for an aryl group.

“Aralkyloxy” refers to a radical bonded through an oxygen atom of theformula —O— aralkyl, where aralkyl is as defined above.

“Aralkenyl” refers to a radical of the formula —R^(d)-aryl where R^(d)is an alkenylene chain as defined above. The aryl part of the aralkenylradical is optionally substituted as described above for an aryl group.The alkenylene chain part of the aralkenyl radical is optionallysubstituted as defined above for an alkenylene group.

“Aralkynyl” refers to a radical of the formula —R^(e)-aryl, where R^(e)is an alkynylene chain as defined above. The aryl part of the aralkynylradical is optionally substituted as described above for an aryl group.The alkynylene chain part of the aralkynyl radical is optionallysubstituted as defined above for an alkynylene chain.

“Cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclichydrocarbon radical consisting solely of carbon and hydrogen atoms,which includes fused or bridged ring systems, having from three tofifteen carbon atoms. In certain embodiments, a cycloalkyl comprisesthree to ten carbon atoms. In other embodiments, a cycloalkyl comprisesfive to seven carbon atoms. The cycloalkyl is attached to the rest ofthe molecule by a single bond. Cycloalkyls are saturated, (i.e.,containing single C—C bonds only) or partially unsaturated (i.e.,containing one or more double bonds or triple bonds.) Examples ofmonocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In certainembodiments, a cycloalkyl comprises three to eight carbon atoms (e.g.,C₃-C₈ cycloalkyl). In other embodiments, a cycloalkyl comprises three toseven carbon atoms (e.g., C₃-C₇ cycloalkyl). In other embodiments, acycloalkyl comprises three to six carbon atoms (e.g., C₃-C₆ cycloalkyl).In other embodiments, a cycloalkyl comprises three to five carbon atoms(e.g., C₃-C₅ cycloalkyl). In other embodiments, a cycloalkyl comprisesthree to four carbon atoms (e.g., C₃-C₄ cycloalkyl). A partiallyunsaturated cycloalkyl is also referred to as “cycloalkenyl.” Examplesof monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl,cycloheptenyl, and cyclooctenyl. Polycyclic cycloalkyl radicals include,for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl),norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and thelike. Unless stated otherwise specifically in the specification, theterm “cycloalkyl” is meant to include cycloalkyl radicals that areoptionally substituted by one or more substituents selected from alkyl,alkenyl, alkynyl, halo, haloalkyl, oxo, thioxo, cyano, nitro, aryl,aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl,heteroarylalkyl, —R^(b)—OR^(a), —R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a),—R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂, —R^(b)C(O)R^(a),—R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)R^(a) (where t is 1 or 2), and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, eachR^(b) is independently a direct bond or a straight or branched alkyleneor alkenylene chain, and R^(c) is a straight or branched alkylene oralkenylene chain.

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodosubstituents.

“Haloalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above.

“Haloalkoxy” refers to an alkoxy radical, as defined above, that issubstituted by one or more halo radicals, as defined above.

“Fluoroalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more fluoro radicals, as defined above, forexample, trifluoromethyl, difluoromethyl, fluoromethyl,2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. Thealkyl part of the fluoroalkyl radical are optionally substituted asdefined above for an alkyl group.

“Heterocycloalkyl” refers to a stable 3- to 18-membered non-aromaticring radical that comprises two to twelve carbon atoms and from one tosix heteroatoms selected from nitrogen, oxygen and sulfur. Unless statedotherwise specifically in the specification, the heterocycloalkylradical is a monocyclic, bicyclic, tricyclic, or tetracyclic ringsystem, which include fused, spiro, or bridged ring systems. Theheteroatoms in the heterocycloalkyl radical are optionally oxidized. Oneor more nitrogen atoms, if present, are optionally quaternized. Theheterocycloalkyl radical is partially or fully saturated. In someembodiments, the heterocycloalkyl is attached to the rest of themolecule through any atom of the ring(s). Examples of suchheterocycloalkyl radicals include, but are not limited to, dioxolanyl,thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in thespecification, the term “heterocycloalkyl” is meant to includeheterocycloalkyl radicals as defined above that are optionallysubstituted by one or more substituents selected from alkyl, alkenyl,alkynyl, halo, haloalkyl, oxo, thioxo, cyano, nitro, aryl, aralkyl,aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl,heteroarylalkyl, —R^(b)—OR^(a), —R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a),—R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a),—R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)R^(a) (where t is 1 or 2), and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, eachR^(b) is independently a direct bond or a straight or branched alkyleneor alkenylene chain, and R^(c) is a straight or branched alkylene oralkenylene chain.

“Heteroaryl” refers to a radical derived from a 3- to 18-memberedaromatic ring radical that comprises one to seventeen carbon atoms andfrom one to six heteroatoms selected from nitrogen, oxygen and sulfur.As used herein, the heteroaryl radical is a monocyclic, bicyclic,tricyclic or tetracyclic ring system, wherein at least one of the ringsin the ring system is fully unsaturated, i.e., it contains a cyclic,delocalized (4n+2) π-electron system in accordance with the Hückeltheory. Heteroaryl includes fused or bridged ring systems. Theheteroatom(s) in the heteroaryl radical is optionally oxidized. One ormore nitrogen atoms, if present, are optionally quaternized. Theheteroaryl is attached to the rest of the molecule through any atom ofthe ring(s). Unless stated otherwise specifically in the specification,the term “heteroaryl” is meant to include heteroaryl radicals as definedabove which are optionally substituted by one or more substituentsselected from alkyl, alkenyl, alkynyl, halo, haloalkyl, oxo, thioxo,cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl,heterocycloalkyl, heteroaryl, heteroarylalkyl, —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,—R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a),—R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)R^(a) (where t is 1 or 2), and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, eachR^(b) is independently a direct bond or a straight or branched alkyleneor alkenylene chain, and R^(c) is a straight or branched alkylene oralkenylene chain.

“N-heteroaryl” refers to a heteroaryl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe heteroaryl radical to the rest of the molecule is through a nitrogenatom in the heteroaryl radical. An N-heteroaryl radical is optionallysubstituted as described above for heteroaryl radicals.

“C-heteroaryl” refers to a heteroaryl radical as defined above and wherethe point of attachment of the heteroaryl radical to the rest of themolecule is through a carbon atom in the heteroaryl radical. AC-heteroaryl radical is optionally substituted as described above forheteroaryl radicals.

“Heteroaryloxy” refers to radical bonded through an oxygen atom of theformula —O-heteroaryl, where heteroaryl is as defined above.

“Heteroarylalkyl” refers to a radical of the formula —R^(c)-heteroaryl,where R^(c) is an alkylene chain as defined above. If the heteroaryl isa nitrogen-containing heteroaryl, the heteroaryl is optionally attachedto the alkyl radical at the nitrogen atom. The alkylene chain of theheteroarylalkyl radical is optionally substituted as defined above foran alkylene chain. The heteroaryl part of the heteroarylalkyl radical isoptionally substituted as defined above for a heteroaryl group.

“Heteroarylalkoxy” refers to a radical bonded through an oxygen atom ofthe formula —O—R^(c)-heteroaryl, where R^(c) is an alkylene chain asdefined above. If the heteroaryl is a nitrogen-containing heteroaryl,the heteroaryl is optionally attached to the alkyl radical at thenitrogen atom. The alkylene chain of the heteroarylalkoxy radical isoptionally substituted as defined above for an alkylene chain. Theheteroaryl part of the heteroarylalkoxy radical is optionallysubstituted as defined above for a heteroaryl group.

In some embodiments, the compounds disclosed herein contain one or moreasymmetric centers and thus give rise to enantiomers, diastereomers, andother stereoisomeric forms that are defined, in terms of absolutestereochemistry, as (R)- or (S)-. Unless stated otherwise, it isintended that all stereoisomeric forms of the compounds disclosed hereinare contemplated by this disclosure. When the compounds described hereincontain alkene double bonds, and unless specified otherwise, it isintended that this disclosure includes both E and Z geometric isomers(e.g., cis or trans.) Likewise, all possible isomers, as well as theirracemic and optically pure forms, and all tautomeric forms are alsointended to be included. The term “geometric isomer” refers to E or Zgeometric isomers (e.g., cis or trans) of an alkene double bond. Theterm “positional isomer” refers to structural isomers around a centralring, such as ortho-, meta-, and para-isomers around a benzene ring.

A “tautomer” refers to a molecule wherein a proton shift from one atomof a molecule to another atom of the same molecule is possible. Incertain embodiments, the compounds presented herein exist as tautomers.In circumstances where tautomerization is possible, a chemicalequilibrium of the tautomers will exist. The exact ratio of thetautomers depends on several factors, including physical state,temperature, solvent, and pH. Some examples of tautomeric equilibriuminclude:

“Optional” or “optionally” means that a subsequently described event orcircumstance may or may not occur and that the description includesinstances when the event or circumstance occurs and instances in whichit does not. For example, “optionally substituted aryl” means that thearyl radical are or are not substituted and that the descriptionincludes both substituted aryl radicals and aryl radicals having nosubstitution.

“Pharmaceutically acceptable salt” includes both acid and base additionsalts. A pharmaceutically acceptable salt of any one of the pyrazolecompounds described herein is intended to encompass any and allpharmaceutically suitable salt forms. Preferred pharmaceuticallyacceptable salts of the compounds described herein are pharmaceuticallyacceptable acid addition salts, and pharmaceutically acceptable baseaddition salts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid,hydrofluoric acid, phosphorous acid, and the like. Also included aresalts that are formed with organic acids such as aliphatic mono- anddicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoicacids, alkanedioic acids, aromatic acids, aliphatic and aromaticsulfonic acids, etc. and include, for example, acetic acid,trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, and the like. Exemplary salts thus include sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates,monohydrogenphosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates,trifluoroacetates, propionates, caprylates, isobutyrates, oxalates,malonates, succinate suberates, sebacates, fumarates, maleates,mandelates, benzoates, chlorobenzoates, methylbenzoates,dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates,phenylacetates, citrates, lactates, malates, tartrates,methanesulfonates, and the like. Also contemplated are salts of aminoacids, such as arginates, gluconates, and galacturonates (see, forexample, Berge S. M. et al., “Pharmaceutical Salts,” Journal ofPharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basiccompounds are prepared by contacting the free base forms with asufficient amount of the desired acid to produce the salt.

“Pharmaceutically acceptable base addition salt” refers to those saltsthat retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. In some embodiments, pharmaceutically acceptable baseaddition salts are formed with metals or amines, such as alkali andalkaline earth metals or organic amines. Salts derived from inorganicbases include, but are not limited to, sodium, potassium, lithium,ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminumsalts, and the like. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, for example,isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol,2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine,caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine,hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline,N-methylglucamine, glucosamine, methylglucamine, theobromine, purines,piperazine, piperidine, N-ethylpiperidine, polyamine resins, and thelike. See Berge et al., supra.

As used herein, “treatment” or “treating” or “palliating” or“ameliorating” are used interchangeably herein. These terms refer to anapproach for obtaining beneficial or desired results including but notlimited to therapeutic benefit and/or a prophylactic benefit. By“therapeutic benefit” is meant eradication or amelioration of theunderlying disorder being treated. Also, a therapeutic benefit isachieved with the eradication or amelioration of one or more of thephysiological symptoms associated with the underlying disorder such thatan improvement is observed in the patient, notwithstanding that thepatient is still afflicted with the underlying disorder. Forprophylactic benefit, the compositions are administered to a patient atrisk of developing a particular disease, or to a patient reporting oneor more of the physiological symptoms of a disease, even though adiagnosis of this disease has not been made.

Compounds

In some embodiments, the compounds of Formula (I), (I′), (Ia), (Ib),(Ic), or (II) described herein, and compositions comprising thesecompounds, are useful for the treatment of cancer. In some embodiments,the compounds of Formula (I), (I′), (Ia), (Ib), (Ic), or (II) describedherein, and compositions comprising these compounds, are useful for thetreatment of an infectious disease.

In some embodiments is a compound of Formula (I):

wherein:

-   -   R¹ is

-   -   R² is —C(O)R⁸;    -   R³ is H, —C(O)R⁹, or —C(O)OR⁹;    -   R⁴ is H;    -   R⁵ is H, C₃₋₂₂alkyl, C₃₋₂₂alkenyl, C₃₋₂₂alkynyl, C₃₋₂₂haloalkyl,        —C₁₋₆alkyl-OC(O)C₁₋₂₂alkyl, C₃₋₈cycloalkyl, C₆₋₁₀aryl,        —C₁₋₈alkyl-C₆₋₁₀aryl, C₂₋₉heteroaryl, or        —C₁₋₈alkyl-C₂₋₉heteroaryl, wherein C₆₋₁₀aryl,        —C₁₋₈alkyl-C₆₋₁₀aryl, C₂₋₉heteroaryl, or        —C₁₋₈alkyl-C₂₋₉heteroaryl are optionally substituted with 1, 2,        3, or 4 R¹⁴;    -   R⁶ is C₃₋₂₂alkyl, C₃₋₂₂alkenyl, C₃₋₂₂alkynyl, C₃₋₂₂haloalkyl,        —C₁₋₆alkyl-OC(O)C₁₋₂₂alkyl, C₃₋₈cycloalkyl, C₆₋₁₀aryl,        —C₁₋₈alkyl-C₆₋₁₀aryl, C₂₋₉heteroaryl, or        —C₁₋₈alkyl-C₂₋₉heteroaryl, wherein C₆₋₁₀aryl,        —C₁₋₈alkyl-C₆₋₁₀aryl, C₂₋₉heteroaryl, or        —C₁₋₈alkyl-C₂₋₉heteroaryl are optionally substituted with 1, 2,        3, or 4 R¹⁴;    -   each R⁷ is independently selected from halogen, C₁₋₈alkyl,        C₁₋₈haloalkyl, and C₁₋₈alkoxy;    -   R⁸ is C₃₋₂₂alkyl, C₃₋₂₂alkenyl, C₃₋₂₂alkynyl, C₃₋₂₂haloalkyl,        C₃₋₈cycloalkyl, C₆₋₁₀aryl, —C₁₋₈alkyl-C₆₋₁₀aryl, C₂₋₉heteroaryl,        or —C₁₋₈alkyl-C₂₋₉heteroaryl, wherein C₆₋₁₀aryl,        —C₁₋₈alkyl-C₆₋₁₀aryl, C₂₋₉heteroaryl, or        —C₁₋₈alkyl-C₂₋₉heteroaryl are optionally substituted with 1, 2,        3, or 4 R¹⁴;    -   R⁹ is C₁₋₁₂alkyl;    -   R¹⁰ and R¹¹ are each independently H or C₁₋₁₂alkyl; or R¹⁰ and        R¹¹ form a 5- or 6-membered cycloalkyl ring or a 5- or        6-membered heterocycloalkyl ring, wherein the 5- or 6-membered        cycloalkyl ring or the 5- or 6-membered heterocycloalkyl ring        are optionally substituted with one or two R¹³;    -   R¹² is H or C₁₋₁₂alkyl;    -   each R¹³ is independently selected from C₁₋₁₂alkyl;    -   each R¹⁴ is independently selected from halogen, C₁₋₈alkyl        C₁₋₈haloalkyl C₁₋₈alkoxy, and —C(O)R¹³;    -   m is 0 or 1;    -   n is 0, 1, 2, 3, or 4; and    -   p is 0 or 1;        or a pharmaceutically acceptable salt thereof.

In some embodiments is a compound of Formula (I′):

wherein:

-   -   R¹ is

-   -   R² is —C(O)R⁸;    -   R³ is H, —C(O)R⁹, or —C(O)OR⁹;    -   R⁴ is H;    -   R⁵ is H, C₃₋₁₈alkyl, C₃₋₁₈alkenyl, C₃₋₁₈alkynyl, C₃₋₁₈haloalkyl,        —C₁₋₄alkyl-OC(O)C₁₋₈alkyl, C₃₋₈cycloalkyl, C₆₋₁₀aryl,        —C₁₋₈alkyl-C₆₋₁₀aryl, C₂₋₉heteroaryl, or        —C₁₋₈alkyl-C₂₋₉heteroaryl, wherein C₆₋₁₀aryl,        —C₁₋₈alkyl-C₆₋₁₀aryl, C₂₋₉heteroaryl, or        —C₁₋₈alkyl-C₂₋₉heteroaryl are optionally substituted with 1, 2,        3, or 4 R¹⁴;    -   R⁶ is C₃₋₁₈alkyl, C₃₋₁₈alkenyl, C₃₋₁₈alkynyl, C₃₋₁₈haloalkyl,        —C₁₋₄alkyl-OC(O)C₁₋₈alkyl, C₃₋₈cycloalkyl, C₆₋₁₀aryl,        —C₁₋₈alkyl-C₆₋₁₀aryl C₂₋₉heteroaryl, or        —C₁₋₈alkyl-C₂₋₉heteroaryl, wherein C₆₋₁₀aryl,        —C₁₋₈alkyl-C₆₋₁₀aryl, C₂₋₉heteroaryl, or        —C₁₋₈alkyl-C₂₋₉heteroaryl are optionally substituted with 1, 2,        3, or 4 R¹⁴;    -   each R⁷ is independently selected from halogen, C₁₋₈alkyl,        C₁₋₈haloalkyl, and C₁₋₈alkoxy;    -   R⁸ is C₃₋₁₈alkyl, C₃₋₁₈alkenyl, C₃₋₁₈alkynyl, C₃₋₁₈haloalkyl,        C₃₋₈cycloalkyl, C₆₋₁₀aryl, —C₁₋₈alkyl-C₆₋₁₀aryl, C₂₋₉heteroaryl,        or —C₁₋₈alkyl-C₂₋₉heteroaryl, wherein C₆₋₁₀aryl,        —C₁₋₈alkyl-C₆₋₁₀aryl, C₂₋₉heteroaryl, or        —C₁₋₈alkyl-C₂₋₉heteroaryl are optionally substituted with 1, 2,        3, or 4 R¹⁴;    -   R⁹ is C₁₋₁₂alkyl;    -   R¹⁰ and R¹¹ are each independently H or C₁₋₁₂alkyl; or R¹⁰ and        R¹¹ form a 5- or 6-membered cycloalkyl ring or a 5- or        6-membered heterocycloalkyl ring, wherein the 5- or 6-membered        cycloalkyl ring or the 5- or 6-membered heterocycloalkyl ring        are optionally substituted with one or two R¹³;    -   R¹² is H or C₁₋₁₂alkyl;    -   each R¹³ is independently selected from C₁₋₁₂alkyl;    -   each R¹⁴ is independently selected from halogen, C₁₋₈alkyl,        C₁₋₈haloalkyl, C₁₋₈alkoxy, and —C(O)R¹³;    -   m is 0 or 1;    -   n is 0, 1, 2, 3, or 4; and    -   p is 0 or 1;    -   or a pharmaceutically acceptable salt thereof.

In another embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R¹ is

In another embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R¹ is

R⁵ is C₃₋₁₈alkyl, and R⁶ is C₃₋₁₈alkyl. In another embodiment is acompound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R¹ is

R⁵ is C₃₋₁₆alkyl, and R⁶ is C₃₋₁₆alkyl. In another embodiment is acompound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R¹ is

R⁵ is C₃₋₁₅alkyl, and R⁶ is C₃₋₁₅alkyl. In another embodiment is acompound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R¹ is

R⁵ is C₃₋₁₂alkyl, and R⁶ is C₃₋₁₂alkyl. In another embodiment is acompound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R¹ is

R⁵ is C₆₋₁₅alkyl, and R⁶ is C₆₋₁₅alkyl. In another embodiment is acompound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R¹ is

R⁵ is C₆₋₁₄alkyl, and R⁶ is C₆₋₁₄alkyl. In another embodiment is acompound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R¹ is

R⁵ is C₆₋₁₂alkyl, and R⁶ is C₆₋₁₂alkyl. In another embodiment is acompound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R¹ is

R⁵ is C₆₋₁₀alkyl, and R⁶ is C₆₋₁₀alkyl. In another embodiment is acompound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R¹ is

R⁵ is C₃₋₁₈alkyl, and R⁶ is C₃₋₁₈alkyl. In another embodiment is acompound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R¹ is

R⁵ is C₃₋₁₅alkyl, and R⁶ is C₃₋₁₅alkyl. In another embodiment is acompound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R¹ is

R⁵ is C₆₋₁₅alkyl, and R⁶ is C₆₋₁₅alkyl. In another embodiment is acompound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R¹ is

R⁵ is C₆₋₁₂alkyl, and R⁶ is C₆₋₁₂alkyl. In another embodiment is acompound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R¹ is

R⁵ is C₆₋₁₀alkenyl, and R⁶ is C₆₋₁₀alkenyl. In another embodiment is acompound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R¹ is

R⁵ is C₃₋₁₈alkynyl and R⁶ is C₃₋₁₈alkynyl. In another embodiment is acompound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R¹ is

R⁵ is C₃₋₁₅alkynyl, and R⁶ is C₃₋₁₅alkynyl. In another embodiment is acompound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R¹ is

R⁵ is C₆₋₁₅alkynyl, and R⁶ is C₆₋₁₅alkynyl. In another embodiment is acompound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R¹ is

R⁵ is C₆₋₁₂alkynyl, and R⁶ is C₆₋₁₂alkynyl. In another embodiment is acompound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R¹ is

R⁵ is C₆₋₁₀alkynyl, and R⁶ is C₆₋₁₀alkynyl. In another embodiment is acompound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R¹ is

R⁵ is C₃₋₁₈haloalkyl, and R⁶ is C₃₋₁₈haloalkyl. In another embodiment isa compound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R¹ is

R⁵ is C₃₋₁₅haloalkyl, and R⁶ is C₃₋₁₅haloalkyl. In another embodiment isa compound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R¹ is

R⁵ is C₆₋₁₅haloalkyl, and R⁶ is C₆₋₁₅haloalkyl. In another embodiment isa compound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R¹ is

R⁵ is C₆₋₁₂haloalkyl and R⁶ is C₆₋₁₂haloalkyl. In another embodiment isa compound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R¹ is

R⁵ is C₆₋₁₀haloalkyl, and R⁶ is C₆₋₁₀haloalkyl. In another embodiment isa compound of Formula (I), or a pharmaceutically acceptable saltthereof, wherein R¹ is

R⁵ is —C₁₋₆alkyl-OC(O)C₁₋₂₂alkyl, and R⁶ is —C₁₋₆alkyl-OC(O)C₁₋₂₂alkyl.In another embodiment is a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein R¹ is

R⁵ is —C₁₋₄alkyl-OC(O)C₁₋₁₆alkyl, and R⁶ is —C₁₋₄alkyl-OC(O)C₁₋₁₆alkyl.In another embodiment is a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein R¹ is

R⁵ is —C₁₋₄alkyl-OC(O)C₁₋₁₂alkyl, and R⁶ is —C₁₋₄alkyl-OC(O)C₁₋₁₂alkyl.In another embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R¹ is

R⁵ is —C₁₋₄alkyl-OC(O)C₁₋₈alkyl, and R⁶ is —C₁₋₄alkyl-OC(O)C₁₋₈alkyl. Inanother embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R¹ is

R⁵ is —C₁₋₂alkyl-OC(O)C₁₋₈alkyl, and R⁶ is —C₁₋₂alkyl-OC(O)C₁₋₈alkyl. Inanother embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R¹ is

R⁵ is —CH₂OC(O)C₁₋₈alkyl, and R⁶ is —CH₂OC(O)C₁₋₈alkyl. In anotherembodiment is a compound of Formula (I) or (I′), or a pharmaceuticallyacceptable salt thereof, wherein R¹ is

R⁵ is —C₁₋₄alkyl-OC(O)C₁₋₆alkyl, and R⁶ is —C₁₋₄alkyl-OC(O)C₁₋₆alkyl. Inanother embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R¹ is

R⁵ is —C₁₋₂alkyl-OC(O)C₁₋₆alkyl, and R⁶ is —C₁₋₂alkyl-OC(O)C₁₋₆alkyl. Inanother embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R¹ is

R⁵ is —CH₂OC(O)C₁₋₆alkyl, and R⁶ is —CH₂OC(O)C₁₋₆alkyl. In anotherembodiment is a compound of Formula (I) or (I′), or a pharmaceuticallyacceptable salt thereof, wherein R¹ is

R⁵ is —C₁₋₄alkyl-OC(O)C₁₋₄alkyl, and R⁶ is —C₁₋₄alkyl-OC(O)C₁₋₄alkyl. Inanother embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R¹ is

R⁵ is —C₁₋₂alkyl-OC(O)C₁₋₄alkyl, and R⁶ is —C₁₋₂alkyl-OC(O)C₁₋₄alkyl. Inanother embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R¹ is

R⁵ is —CH₂OC(O)C₁₋₄alkyl, and R⁶ is —CH₂OC(O)C₁₋₄alkyl. In anotherembodiment is a compound of Formula (I) or (I′), or a pharmaceuticallyacceptable salt thereof, wherein R¹ is

R⁵ is —C₁₋₄alkyl-OC(O)C(CH₃)₃, and R⁶ is —C₁₋₄alkyl-OC(O)C(CH₃)₃. Inanother embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R¹ is

R⁵ is —C₁₋₂alkyl-OC(O)C(CH₃)₃, and R⁶ is —C₁₋₂alkyl-OC(O)C(CH₃)₃. Inanother embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R¹ is

R⁵ is —CH₂OC(O)C(CH₃)₃, and R⁶ is —CH₂OC(O)C(CH₃)₃. In anotherembodiment is a compound of Formula (I) or (I′), or a pharmaceuticallyacceptable salt thereof, wherein R¹ is

R⁵ is C₃₋₈cycloalkyl, and R⁶ is C₃₋₈cycloalkyl. In another embodiment isa compound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R¹ is

R⁵ is C₃₋₆cycloalkyl, and R⁶ is C₃₋₆cycloalkyl. In another embodiment isa compound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R¹ is

R⁵ is unsubstituted C₆₋₁₀aryl, and R⁶ is unsubstituted C₆₋₁₀aryl. Inanother embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R¹ is

R⁵ is C₆₋₁₀aryl substituted with 1 or 2 R¹⁴, and R⁶ is C₆₋₁₀arylsubstituted with 1 or 2 R¹⁴. In another embodiment is a compound ofFormula (I) or (I′), or a pharmaceutically acceptable salt thereof,wherein R¹ is

R⁵ is unsubstituted phenyl, and R⁶ is unsubstituted phenyl. In anotherembodiment is a compound of Formula (I) or (I′), or a pharmaceuticallyacceptable salt thereof, wherein R¹ is

R⁵ is phenyl substituted with 1 or 2 R¹⁴ and R⁶ is phenyl substitutedwith 1 or 2 R¹⁴. In another embodiment is a compound of Formula (I) or(I′), or a pharmaceutically acceptable salt thereof, wherein R¹ is

R⁵ is unsubstituted —C₁₋₈alkyl-C₆₋₁₀aryl, and R⁶ is unsubstituted—C₁₋₈alkyl-C₆₋₁₀aryl. In another embodiment is a compound of Formula (I)or (I′), or a pharmaceutically acceptable salt thereof, wherein R¹ is

R⁵ is —C₁₋₈alkyl-C₆₋₁₀aryl substituted with 1 or 2 R¹⁴, and R⁶ is—C₁₋₈alkyl-C₆₋₁₀aryl substituted with 1 or 2 R¹⁴. In another embodimentis a compound of Formula (I) or (I′), or a pharmaceutically acceptablesalt thereof, wherein R¹ is

R⁵ is unsubstituted —CH₂-phenyl, and R⁶ is unsubstituted —CH₂-phenyl. Inanother embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R¹ is

R⁵ is —CH₂-phenyl substituted with 1 or 2 R¹⁴, and R⁶ is —CH₂-phenylsubstituted with 1 or 2 R¹⁴. In another embodiment is a compound ofFormula (I) or (I′), or a pharmaceutically acceptable salt thereof,wherein R¹ is

R⁵ is unsubstituted C₂₋₉heteroaryl, and R⁶ is unsubstitutedC₂₋₉heteroaryl. In another embodiment is a compound of Formula (I) or(I′), or a pharmaceutically acceptable salt thereof, wherein R¹ is

R⁵ is C₂₋₉heteroaryl substituted with 1 or 2 R¹⁴, and R⁶ isC₂₋₉heteroaryl substituted with 1 or 2 R¹⁴. In another embodiment is acompound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R¹ is

R⁵ is unsubstituted —C₁₋₈alkyl-C₂₋₉heteroaryl, and R⁶ is unsubstituted—C₁₋₈alkyl-C₂₋₉heteroaryl. In another embodiment is a compound ofFormula (I) or (I′), or a pharmaceutically acceptable salt thereof,wherein R¹ is

R⁵ is —C₁₋₈alkyl-C₂₋₉heteroaryl substituted with 1 or 2 R¹⁴, and R⁶ is—C₁₋₈alkyl-C₂₋₉heteroaryl substituted with 1 or 2 R¹⁴.

In another embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R¹ is

R⁵ is H, and R⁶ is C₃₋₁₈alkyl. In another embodiment is a compound ofFormula (I) or (I′), or a pharmaceutically acceptable salt thereof,wherein R¹ is

R⁵ is H, and R⁶ is C₆₋₁₅alkyl. In another embodiment is a compound ofFormula (I) or (I′), or a pharmaceutically acceptable salt thereof,wherein R¹ is

R⁵ is H, and R⁶ is C₆₋₁₀alkyl. In another embodiment is a compound ofFormula (I) or (I′), or a pharmaceutically acceptable salt thereof,wherein R¹ is

R⁵ is H, and R⁶ is C₃₋₁₈alkenyl. In another embodiment is a compound ofFormula (I) or (I′), or a pharmaceutically acceptable salt thereof,wherein R¹ is

R⁵ is H, and R⁶ is C₆₋₁₅alkenyl. In another embodiment is a compound ofFormula (I) or (I′), or a pharmaceutically acceptable salt thereof,wherein R¹ is

R⁵ is H, and R⁶ is C₆₋₁₀alkenyl. In another embodiment is a compound ofFormula (I) or (I′), or a pharmaceutically acceptable salt thereof,wherein R¹ is

R⁵ is H, and R⁶ is C₃₋₁₈alkynyl. In another embodiment is a compound ofFormula (I) or (I′), or a pharmaceutically acceptable salt thereof,wherein R¹ is

R⁵ is H, and R⁶ is C₆₋₁₅alkynyl. In another embodiment is a compound ofFormula (I) or (I′), or a pharmaceutically acceptable salt thereof,wherein R¹ is

R⁵ is H, and R⁶ is C₆₋₁₀alkynyl. In another embodiment is a compound ofFormula (I) or (I′), or a pharmaceutically acceptable salt thereof,wherein R¹ is

R⁵ is H, and R⁶ is C₃₋₁₈haloalkyl. In another embodiment is a compoundof Formula (I) or (I′), or a pharmaceutically acceptable salt thereof,wherein R¹ is

R⁵ is H, and R⁶ is C₆₋₁₅haloalkyl. In another embodiment is a compoundof Formula (I) or (I′), or a pharmaceutically acceptable salt thereof,wherein R¹ is

R⁵ is H, and R⁶ is C₆₋₁₀haloalkyl. In another embodiment is a compoundof Formula (I) or (I′), or a pharmaceutically acceptable salt thereof,wherein R¹ is

R⁵ is H, and R⁶ is —C₁₋₄alkyl-OC(O)C₁₋₈alkyl. In another embodiment is acompound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R¹ is

R⁵ is H, and R⁶ is —C₁₋₂alkyl-OC(O)C₁₋₈alkyl. In another embodiment is acompound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R¹ is

R⁵ is H, and R⁶ is-CH₂OC(O)C₁₋₈alkyl. In another embodiment is acompound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R¹ is

R⁵ is H, and K is —C₁₋₄alkyl-OC(O)C₁₋₄alkyl. In another embodiment is acompound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R¹ is

R⁵ is H, and R⁶ is —C₁₋₂alkyl-OC(O)C₁₋₄alkyl. In another embodiment is acompound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R¹ is

R⁵ is H, and R⁶ is —CH₂OC(O)C₁₋₄alkyl. In another embodiment is acompound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R¹ is

R⁵ is H, and R⁶ is —C₁₋₄alkyl-OC(O)C(CH₃)₃. In another embodiment is acompound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R¹ is

R⁵ is H, and R⁶ is —C₁₋₂alkyl-OC(O)C(CH₃)₃. In another embodiment is acompound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R¹ is

R⁵ is H, and R⁶ is —CH₂OC(O)C(CH₃)₃.

In another embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R¹ is

In another embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R¹ is

and m is 1. In another embodiment is a compound of Formula (I) or (I′),or a pharmaceutically acceptable salt thereof, wherein R¹ is

m is 1, and R¹⁰, R¹¹ and R¹² are each H. In another embodiment is acompound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R¹ is

m is 1 and R¹⁰, R¹¹ and R¹² are each C₁₋₁₂alkyl. In another embodimentis a compound of Formula (I) or (I′), or a pharmaceutically acceptablesalt thereof, wherein R¹ is

m is 1 and R¹⁰, R¹¹ and R¹² are each C₁₋₄alkyl. In another embodiment isa compound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R¹ is

m is 1, and R¹⁰, R¹¹ and R¹² are each —CH₃. In another embodiment is acompound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R¹ is

m is 1, R¹⁰ is C₁₋₁₂alkyl, and R¹¹ and R¹² are each H. In anotherembodiment is a compound of Formula (I) or (I′), or a pharmaceuticallyacceptable salt thereof, wherein R¹ is

m is 1, R¹⁰ is C₁₋₄alkyl, and R¹¹ and R¹² are each H. In anotherembodiment is a compound of Formula (I) or (I′), or a pharmaceuticallyacceptable salt thereof, wherein R¹ is

m is 1, R¹⁰ is —CH₃, and R¹¹ and R¹² are each H. In another embodimentis a compound of Formula (I) or (I′), or a pharmaceutically acceptablesalt thereof, wherein R¹ is

m is 1, R¹⁰ is C₁₋₁₂alkyl, and R¹⁰ and R¹² are each H. In anotherembodiment is a compound of Formula (I) or (I′), or a pharmaceuticallyacceptable salt thereof, wherein R¹ is

m is 1, R¹¹ is C₁₋₄alkyl, and R¹⁰ and R¹² are each H. In anotherembodiment is a compound of Formula (I) or (I′), or a pharmaceuticallyacceptable salt thereof, wherein

m is 1, R¹¹ is —CH₃, and R¹⁰ and R¹² are each H. In another embodimentis a compound of Formula (I) or (I′), or a pharmaceutically acceptablesalt thereof, wherein R¹ is

m is 1, R¹⁰ is H, and R¹¹ and R¹² are each C₁₋₁₂alkyl. In anotherembodiment is a compound of Formula (I) or (I′), or a pharmaceuticallyacceptable salt thereof, wherein R¹ is

m is 1, R¹⁰ is H, and R¹¹ and R¹² are each C₁₋₄alkyl. In anotherembodiment is a compound of Formula (I) or (I′), or a pharmaceuticallyacceptable salt thereof, wherein R¹ is

m is 1, R¹⁰ is H, and R¹¹ and R¹² are each —CH₃. In another embodimentis a compound of Formula (I) or (I′), or a pharmaceutically acceptablesalt thereof, wherein R¹ is

m is 1, R¹¹ is H, and R¹⁰ and R¹² are each C₁₋₁₂alkyl. In anotherembodiment is a compound of Formula (I) or (I′), or a pharmaceuticallyacceptable salt thereof, wherein R¹ is

m is 1, R¹¹ is H, and R¹⁰ and R¹² are each C₁₋₄alkyl. In anotherembodiment is a compound of Formula (I) or (I′), or a pharmaceuticallyacceptable salt thereof, wherein R¹ is

m is 1, R¹¹ is H, and R¹⁰ and R¹² are each —CH₃. In another embodimentis a compound of Formula (I) or (I′), or a pharmaceutically acceptablesalt thereof, wherein R¹ is

m is 1, R is H, and R¹⁰ and R¹¹ form a 5- or 6-membered cycloalkyl ringor a 5- or 6-membered heterocycloalkyl ring, wherein the 5- or6-membered cycloalkyl ring or the 5- or 6-membered heterocycloalkyl ringare optionally substituted with one or two R¹³. In another embodiment isa compound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R¹ is

m is 1, R¹² is H, and R¹⁰ and R¹¹ form a 5- or 6-membered cycloalkylring optionally substituted with one or two R¹³. In another embodimentis a compound of Formula (I) or (I′), or a pharmaceutically acceptablesalt thereof, wherein R¹ is

m is 1, R¹² is H, and R¹⁰ and R¹¹ form a 5- or 6-memberedheterocycloalkyl ring optionally substituted with one or two R¹³. Inanother embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R¹ is

m is 1, R¹² is C₁₋₁₂alkyl, and R¹⁰ and R¹¹ form a 5- or 6-memberedcycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring, wherein the5- or 6-membered cycloalkyl ring or the 5- or 6-memberedheterocycloalkyl ring are optionally substituted with one or two R¹³. Inanother embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R¹ is

m is 1, R¹² is C₁₋₁₂alkyl, and R¹⁰ and R¹¹ form a 5- or 6-memberedcycloalkyl ring optionally substituted with one or two R¹³. In anotherembodiment is a compound of Formula (I) or (I′), or a pharmaceuticallyacceptable salt thereof, wherein R¹ is

m is 1, R¹² is C₁₋₁₂alkyl, and R¹⁰ and R¹¹ form a 5- or 6-memberedheterocycloalkyl ring optionally substituted with one or two R¹³. Inanother embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R¹ is

and m is 0. In another embodiment is a compound of Formula (I) or (I′),or a pharmaceutically acceptable salt thereof, wherein R¹ is

m is 0, and R¹⁰ and R¹¹ are each H. In another embodiment is a compoundof Formula (I) or (I′), or a pharmaceutically acceptable salt thereof,wherein R¹ is

m is 0, and R¹⁰ and R¹¹ are each C₁₋₁₂alkyl. In another embodiment is acompound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R¹ is

m is 0, and R¹⁰ and R¹¹ are each C₁₋₄alkyl. In another embodiment is acompound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R¹ is

m is 0, and R¹⁰ and R¹¹ are each —CH₃. In another embodiment is acompound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R¹ is

m is 0, R¹⁰ is H, and R¹¹ is C₁₋₁₂alkyl. In another embodiment is acompound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R¹ is

m is 0, R¹⁰ is H, and R¹¹ is C₁₋₄alkyl. In another embodiment is acompound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R¹ is

m is 0, R¹⁰ is H, and R¹¹ is —CH₃. In another embodiment is a compoundof Formula (I) or (I′), or a pharmaceutically acceptable salt thereof,wherein R¹ is

m is 0, R¹⁰ is C₁₋₁₂alkyl, and R¹¹ is H. In another embodiment is acompound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R¹ is

m is 0, R¹⁰ is C₁₋₄alkyl, and R¹¹ is H. In another embodiment is acompound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R¹ is

m is 0, R¹⁰ is —CH₃, and R¹¹ is H. In another embodiment is a compoundof Formula (I) or (I′), or a pharmaceutically acceptable salt thereof,wherein R¹ is

m is 0, and R¹⁰ and R¹¹ form a 5- or 6-membered cycloalkyl ring or a 5-or 6-membered heterocycloalkyl ring, wherein the 5- or 6-memberedcycloalkyl ring or the 5- or 6-membered heterocycloalkyl ring areoptionally substituted with one or two R¹³. In another embodiment is acompound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R¹ is

m is 0, and R¹⁰ and R¹¹ form a 5- or 6-membered cycloalkyl ringoptionally substituted with one or two R¹³. In another embodiment is acompound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R¹ is

m is 0, and R¹⁰ and R¹¹ form a 5- or 6-membered heterocycloalkyl ringoptionally substituted with one or two R¹³.

In another embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R¹ is

In another embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R¹ is

and p is 1. In another embodiment is a compound of Formula (I) or (I′),or a pharmaceutically acceptable salt thereof, wherein R¹ is

p is 1, and n is 0. In another embodiment is a compound of Formula (I)or (I′), or a pharmaceutically acceptable salt thereof, wherein R¹ is

p is 1, and n is 1, 2, 3, or 4. In another embodiment is a compound ofFormula (I) or (I′), or a pharmaceutically acceptable salt thereof,wherein R¹ is

p is 1, and n is 1 or 2. In another embodiment is a compound of Formula(I) or (I′), or a pharmaceutically acceptable salt thereof, wherein R¹is

p is 1, and n is 1. In another embodiment is a compound of Formula (I)or (I′), or a pharmaceutically acceptable salt thereof, wherein R¹ is

p is 1, n is 1, and R⁷ is halogen. In another embodiment is a compoundof Formula (I) or (I′), or a pharmaceutically acceptable salt thereof,wherein R¹ is

p is 1, n is 1, and R⁷ is C₁₋₈alkyl. In another embodiment is a compoundof Formula (I) or (I′), or a pharmaceutically acceptable salt thereof,wherein R¹ is

p is 1, n is 1, and R⁷ is C₁₋₈haloalkyl. In another embodiment is acompound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R¹ is

p is 1, n is 1, and R⁷ is C₁₋₈alkoxy. In another embodiment is acompound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R¹ is

and p is 0. In another embodiment is a compound of Formula (I) or (I′),or a pharmaceutically acceptable salt thereof, wherein R¹ is

p is 0, and n is 0. In another embodiment is a compound of Formula (I)or (I′), or a pharmaceutically acceptable salt thereof, wherein R¹ is

p is 0, and n is 1, 2, 3, or 4. In another embodiment is a compound ofFormula (I) or (I′), or a pharmaceutically acceptable salt thereof,wherein R¹ is

p is 0, and n is 1 or 2. In another embodiment is a compound of Formula(I) or (I′), or a pharmaceutically acceptable salt thereof, wherein R¹is

p is 0, and n is 1. In another embodiment is a compound of Formula (I)or (I′), or a pharmaceutically acceptable salt thereof, wherein R¹ is

p is 0, n is 1, and R⁷ is halogen. In another embodiment is a compoundof Formula (I) or (I′), or a pharmaceutically acceptable salt thereof,wherein R¹ is

p is 0, n is 1, and R⁷ is C₁₋₈alkyl. In another embodiment is a compoundof Formula (I) or (I′), or a pharmaceutically acceptable salt thereof,wherein R¹ is

p is 0, n is 1, and R⁷ is C₁₋₈haloalkyl. In another embodiment is acompound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R¹ is

p is 0, n is 1, and R⁷ is C₁₋₈alkoxy.

In another embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R⁸ is C₃₋₁₈alkyl. Inanother embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R⁸ is C₃₋₁₅alkyl. Inanother embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R⁸ is C₃₋₁₂alkyl. Inanother embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R⁸ is C₆₋₁₈alkyl. Inanother embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R⁸ is C₆₋₁₂alkyl. Inanother embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R⁸ is C₆₋₁₀alkyl. Inanother embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R⁸ is C₈₋₁₀alkyl. Inanother embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R⁸ is —(CH₂)₂CH₃. Inanother embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R⁸ is —(CH₂)₃CH₃. Inanother embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R⁸ is —(CH₂)₄CH₃. Inanother embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R⁸ is —(CH₂)₅CH₃. Inanother embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R⁸ is —(CH₂)₆CH₃. Inanother embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R⁸ is —(CH₂)₇CH₃. Inanother embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R⁸ is —(CH₂)₈CH₃. Inanother embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R⁸ is —(CH₂)₉CH₃. Inanother embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R⁸ is —(CH₂)₁₀CH₃. Inanother embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R⁸ is —(CH₂)₁₁CH₃. Inanother embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R⁸ is —(CH₂)₁₂CH₃. Inanother embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R⁸ is —(CH₂)₁₃CH₃. Inanother embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R⁸ is —(CH₂)₁₄CH₃. Inanother embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R⁸ is —(CH₂)₁₅CH₃. Inanother embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R⁸ is —(CH₂)₁₆CH₃. Inanother embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R⁸ is —(CH₂)₁₇CH₃. Inanother embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R⁸ is C₃₋₁₈alkenyl. Inanother embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R⁸ is C₃₋₁₂alkenyl. Inanother embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R⁸ is C₆₋₁₂alkenyl. Inanother embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R⁸ is C₆₋₁₀alkenyl. Inanother embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R⁸ is C₈₋₁₀alkenyl. Inanother embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R⁸ is C₃₋₁₈alkynyl. Inanother embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R⁸ is C₃₋₁₂alkynyl. Inanother embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R⁸ is C₆₋₁₂alkynyl. Inanother embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R⁸ is C₆₋₁₀alkynyl. Inanother embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R⁸ is C₈₋₁₀alkynyl. Inanother embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R⁸ is C₃₋₁₈haloalkyl.In another embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R⁸ is C₃₋₁₂haloalkyl.In another embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R⁸ is C₆₋₁₂haloalkyl.In another embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R⁸ is C₆₋₁₀haloalkyl.In another embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R⁸ is C₈₋₁₀haloalkyl.In another embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R⁸ is C₃₋₈cycloalkyl.In another embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R⁸ is C₃₋₆cycloalkyl.In another embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R⁸ is C₆₋₁₀aryloptionally substituted with 1, 2, 3, or 4 R¹⁴. In another embodiment isa compound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R⁸ is unsubstituted C₆₋₁₀aryl. In another embodiment isa compound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R⁸ is C₆₋₁₀aryl substituted with 1 or 2 R¹⁴. In anotherembodiment is a compound of Formula (I) or (I′), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is phenyl optionally substitutedwith 1, 2, 3, or 4 R¹⁴. In another embodiment is a compound of Formula(I) or (I′), or a pharmaceutically acceptable salt thereof, wherein R⁸is unsubstituted phenyl. In another embodiment is a compound of Formula(I) or (I′), or a pharmaceutically acceptable salt thereof, wherein R⁸is phenyl substituted with 1 or 2 R¹⁴. In another embodiment is acompound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R⁸ is —C₁₋₈alkyl-C₆₋₁₀aryl optionally substituted with1, 2, 3, or 4 R¹⁴. In another embodiment is a compound of Formula (I) or(I′), or a pharmaceutically acceptable salt thereof, wherein R⁸ isunsubstituted —C₁₋₈alkyl-C₆₋₁₀aryl. In another embodiment is a compoundof Formula (I) or (I′), or a pharmaceutically acceptable salt thereof,wherein R⁸ is —C₁₋₈alkyl-C₆₋₁₀aryl substituted with 1 or 2 R¹⁴. Inanother embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R⁸ is —CH₂-phenyloptionally substituted with 1, 2, 3, or 4 R¹⁴. In another embodiment isa compound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R⁸ is unsubstituted —CH₂-phenyl. In another embodimentis a compound of Formula (I) or (I′), or a pharmaceutically acceptablesalt thereof, wherein R⁸ is —CH₂-phenyl substituted with 1 or 2 R¹⁴. Inanother embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R⁸ is C₂₋₉heteroaryloptionally substituted with 1, 2, 3, or 4 R¹⁴. In another embodiment isa compound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R⁸ is unsubstituted C₂₋₉heteroaryl. In anotherembodiment is a compound of Formula (I) or (I′), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₂₋₉heteroaryl substituted with 1or 2 R¹⁴. In another embodiment is a compound of Formula (I) or (I′), ora pharmaceutically acceptable salt thereof, wherein R⁸ is—CH₂—C₂₋₉heteroaryl optionally substituted with 1, 2, 3, or 4 R¹⁴. Inanother embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R⁸ is unsubstituted—CH₂—C₂₋₉heteroaryl. In another embodiment is a compound of Formula (I)or (I′), or a pharmaceutically acceptable salt thereof, wherein R⁸ is—CH₂—C₂₋₉heteroaryl substituted with 1 or 2 R¹⁴.

In another embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R³ is H. In anotherembodiment is a compound of Formula (I) or (I′), or a pharmaceuticallyacceptable salt thereof, wherein R³ is —C(O)R⁹. In another embodiment isa compound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R³ is —C(O)R⁹ and R⁹ is C₁₋₁₀alkyl. In anotherembodiment is a compound of Formula (I) or (I′), or a pharmaceuticallyacceptable salt thereof, wherein R³ is —C(O)R⁹ and R⁹ is C₁₋₆alkyl. Inanother embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R³ is —C(O)R⁹ and R⁹is C₁₋₄alkyl. In another embodiment is a compound of Formula (I) or(I′), or a pharmaceutically acceptable salt thereof, wherein R³ is—C(O)R⁹ and R⁹ is —CH₃. In another embodiment is a compound of Formula(I) or (I′), or a pharmaceutically acceptable salt thereof, wherein R³is —C(O)R⁹ and R⁹ is —CH₂CH₃. In another embodiment is a compound ofFormula (I) or (I′), or a pharmaceutically acceptable salt thereof,wherein R³ is —C(O)OR⁹. In another embodiment is a compound of Formula(I) or (I′), or a pharmaceutically acceptable salt thereof, wherein R³is —C(O)OR⁹ and R⁹ is C₁₋₁₀alkyl. In another embodiment is a compound ofFormula (I) or (I′), or a pharmaceutically acceptable salt thereof,wherein R³ is —C(O)OR⁹ and R⁹ is C₁₋₆alkyl. In another embodiment is acompound of Formula (I) or (I′), or a pharmaceutically acceptable saltthereof, wherein R³ is —C(O)OR⁹ and R⁹ is C₁₋₄alkyl. In anotherembodiment is a compound of Formula (I) or (I′), or a pharmaceuticallyacceptable salt thereof, wherein R³ is —C(O)OR⁹ and R⁹ is —CH₃. Inanother embodiment is a compound of Formula (I) or (I′), or apharmaceutically acceptable salt thereof, wherein R³ is —C(O)OR⁹ and R⁹is —CH₂CH₃.

In some embodiments is a compound of Formula (I′) having the structureof Formula (Ia):

wherein:

-   -   R³ is H, —C(O)R⁹, or —C(O)OR⁹;    -   R⁵ is H, C₃₋₁₈alkyl, C₃₋₁₈alkenyl, C₃₋₁₈alkynyl, C₃₋₁₈haloalkyl,        —C₁₋₄alkyl-OC(O)C₁₋₈alkyl, C₃₋₈cycloalkyl, C₆₋₁₀aryl,        —C₁₋₈alkyl-C₆₋₁₀aryl, C₂₋₉heteroaryl, or        —C₁₋₈alkyl-C₂₋₉heteroaryl, wherein C₆₋₁₀aryl,        —C₁₋₈alkyl-C₆₋₁₀aryl, C₂₋₉heteroaryl, or        —C₁₋₈alkyl-C₂₋₉heteroaryl are optionally substituted with 1, 2,        3, or 4 R¹⁴;    -   R⁶ is C₃₋₁₈alkyl, C₃₋₁₈alkenyl, C₃₋₁₈alkynyl, C₃₋₁₈haloalkyl,        —C₁₋₄alkyl-OC(O)C₁₋₈alkyl, C₃₋₈cycloalkyl, C₆₋₁₀aryl,        —C₁₋₈alkyl-C₆₋₁₀aryl C₂₋₉heteroaryl, or        —C₁₋₈alkyl-C₂₋₉heteroaryl, wherein C₆₋₁₀aryl,        —C₁₋₈alkyl-C₆₋₁₀aryl, C₂₋₉heteroaryl, or        —C₁₋₈alkyl-C₂₋₉heteroaryl are optionally substituted with 1, 2,        3, or 4 R¹⁴;    -   R⁸ is C₃₋₁₈alkyl, C₃₋₁₈alkenyl, C₃₋₁₈alkynyl, C₃₋₁₈haloalkyl,        C₃₋₈cycloalkyl, C₆₋₁₀aryl, —C₁₋₈alkyl-C₆₋₁₀aryl, C₂₋₉heteroaryl,        or —C₁₋₈alkyl-C₂₋₉heteroaryl, wherein C₆₋₁₀aryl,        —C₁₋₈alkyl-C₆₋₁₀aryl, C₂₋₉heteroaryl, or        —C₁₋₈alkyl-C₂₋₉heteroaryl are optionally substituted with 1, 2,        3, or 4 R¹⁴;    -   R⁹ is C₁₋₁₂alkyl;    -   each R¹³ is independently selected from C₁₋₁₂alkyl; and    -   each R¹⁴ is independently selected from halogen, C₁₋₈alkyl,        C₁₋₈haloalkyl, C₁₋₈alkoxy, and —C(O)R¹³;    -   or a pharmaceutically acceptable salt thereof.

In another embodiment is a compound of Formula (Ia), or apharmaceutically acceptable salt thereof, wherein R⁵ is C₃₋₁₈alkyl andR⁶ is C₃₋₁₈alkyl. In another embodiment is a compound of Formula (Ia),or a pharmaceutically acceptable salt thereof, wherein R⁵ is C₃₋₁₅alkyland R⁶ is C₃₋₁₅alkyl. In another embodiment is a compound of Formula(Ia), or a pharmaceutically acceptable salt thereof, wherein R⁵ isC₆₋₁₅alkyl and R⁶ is C₆₋₁₅alkyl. In another embodiment is a compound ofFormula (Ia), or a pharmaceutically acceptable salt thereof, wherein R⁵is C₆₋₁₂alkyl and R⁶ is C₆₋₁₂alkyl. In another embodiment is a compoundof Formula (Ia), or a pharmaceutically acceptable salt thereof, whereinR⁵ is C₆₋₁₀alkyl and R⁶ is C₆₋₁₀alkyl. In another embodiment is acompound of Formula (Ia), or a pharmaceutically acceptable salt thereof,wherein R⁵ is C₃₋₁₈alkenyl and R⁶ is C₃₋₁₈alkenyl. In another embodimentis a compound of Formula (Ia), or a pharmaceutically acceptable saltthereof, wherein R⁵ is C₃₋₁₅alkenyl and R⁶ is C₃₋₁₅alkenyl. In anotherembodiment is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt thereof, wherein R⁵ is C₆₋₁₅alkenyl and R⁶ isC₆₋₁₅alkenyl. In another embodiment is a compound of Formula (Ia), or apharmaceutically acceptable salt thereof, wherein R⁵ is C₆₋₁₂alkenyl andR⁶ is C₆₋₁₂alkenyl. In another embodiment is a compound of Formula (Ia),or a pharmaceutically acceptable salt thereof, wherein R⁵ isC₆₋₁₀alkenyl and R⁶ is C₆₋₁₀alkenyl. In another embodiment is a compoundof Formula (Ia), or a pharmaceutically acceptable salt thereof, whereinR⁵ is C₃₋₁₈alkynyl and R⁶ is C₃₋₁₈alkynyl. In another embodiment is acompound of Formula (Ia), or a pharmaceutically acceptable salt thereof,wherein R⁵ is C₃₋₁₅alkynyl and R⁶ is C₃₋₁₅alkynyl. In another embodimentis a compound of Formula (Ia), or a pharmaceutically acceptable saltthereof, wherein R⁵ is C₆₋₁₅alkynyl and R⁶ is C₆₋₁₅alkynyl. In anotherembodiment is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt thereof, wherein R⁵ is C₆₋₁₂alkynyl and R⁶ isC₆₋₁₂alkynyl. In another embodiment is a compound of Formula (Ia), or apharmaceutically acceptable salt thereof, wherein R⁵ is C₆₋₁₀alkynyl andR⁶ is C₆₋₁₀alkynyl. In another embodiment is a compound of Formula (Ia),or a pharmaceutically acceptable salt thereof, wherein R⁵ isC₃₋₁₈haloalkyl and R⁶ is C₃₋₁₈haloalkyl. In another embodiment is acompound of Formula (Ia), or a pharmaceutically acceptable salt thereof,wherein R⁵ is C₃₋₁₅haloalkyl and R⁶ is C₃₋₁₅haloalkyl. In anotherembodiment is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt thereof, wherein R⁵ is C₆₋₁₅haloalkyl and R⁶ isC₆₋₁₅haloalkyl. In another embodiment is a compound of Formula (Ia), ora pharmaceutically acceptable salt thereof, wherein R⁵ is C₆₋₁₂haloalkyland R⁶ is C₆₋₁₂haloalkyl. In another embodiment is a compound of Formula(Ia), or a pharmaceutically acceptable salt thereof, wherein R⁵ isC₆₋₁₀haloalkyl and R⁶ is C₆₋₁₀haloalkyl. In another embodiment is acompound of Formula (Ia), or a pharmaceutically acceptable salt thereof,wherein R⁵ is —C₁₋₄alkyl-OC(O)C₁₋₈alkyl and R⁶ is—C₁₋₄alkyl-OC(O)C₁₋₈alkyl. In another embodiment is a compound ofFormula (Ia), or a pharmaceutically acceptable salt thereof, wherein R⁵is —C₁₋₂alkyl-OC(O)C₁₋₈alkyl and R⁶ is —C₁₋₂alkyl-OC(O)C₁₋₈alkyl. Inanother embodiment is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt thereof, wherein R⁵ is —CH₂OC(O)C₁₋₈alkyl and R⁶ is—CH₂OC(O)C₁₋₈alkyl. In another embodiment is a compound of Formula (Ia),or a pharmaceutically acceptable salt thereof, wherein R⁵ is—C₁₋₄alkyl-OC(O)C₁₋₆alkyl and R⁶ is —C₁₋₄alkyl-OC(O)C₁₋₆alkyl. Inanother embodiment is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt thereof, wherein R⁵ is —C₁₋₂alkyl-OC(O)C₁₋₆alkyl and R⁶is —C₁₋₂alkyl-OC(O)C₁₋₆alkyl. In another embodiment is a compound ofFormula (Ia), or a pharmaceutically acceptable salt thereof, wherein R⁵is —CH₂OC(O)C₁₋₆alkyl and R⁶ is —CH₂OC(O)C₁₋₆alkyl. In anotherembodiment is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt thereof, wherein R⁵ is —C₁₋₄alkyl-OC(O)C₁₋₄alkyl and R⁶is —C₁₋₄alkyl-OC(O)C₁₋₄alkyl. In another embodiment is a compound ofFormula (Ia), or a pharmaceutically acceptable salt thereof, wherein R⁵is —C₁₋₂alkyl-OC(O)C₁₋₄alkyl and R⁶ is —C₁₋₂alkyl-OC(O)C₁₋₄alkyl. Inanother embodiment is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt thereof, wherein R⁵ is —CH₂OC(O)C₁₋₄alkyl and R⁶ is—CH₂OC(O)C₁₋₄alkyl. In another embodiment is a compound of Formula (Ia),or a pharmaceutically acceptable salt thereof, wherein R⁵ is—C₁₋₄alkyl-OC(O)C(CH₃)₃ and R⁶ is —C₁₋₄alkyl-OC(O)C(CH₃)₃. In anotherembodiment is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt thereof, wherein R⁵ is —C₁₋₂alkyl-OC(O)C(CH₃)₃ and R⁶ is—C₁₋₂alkyl-OC(O)C(CH₃)₃. In another embodiment is a compound of Formula(Ia), or a pharmaceutically acceptable salt thereof, wherein R⁵ is—CH₂OC(O)C(CH₃)₃, and R⁶ is —CH₂OC(O)C(CH₃)₃. In another embodiment is acompound of Formula (Ia), or a pharmaceutically acceptable salt thereof,wherein R⁵ is C₃₋₈cycloalkyl and R⁶ is C₃₋₈cycloalkyl. In anotherembodiment is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt thereof, wherein R⁵ is C₃₋₆cycloalkyl and R⁶ isC₃₋₆cycloalkyl. In another embodiment is a compound of Formula (Ia), ora pharmaceutically acceptable salt thereof, wherein R⁵ is unsubstitutedC₆₋₁₀aryl and R⁶ is unsubstituted C₆₋₁₀aryl. In another embodiment is acompound of Formula (Ia), or a pharmaceutically acceptable salt thereof,wherein R⁵ is C₆₋₁₀aryl substituted with 1 or 2 R¹⁴, and R⁶ is C₆₋₁₀arylsubstituted with 1 or 2 R¹⁴. In another embodiment is a compound ofFormula (Ia), or a pharmaceutically acceptable salt thereof, wherein R⁵is unsubstituted phenyl, and R⁶ is unsubstituted phenyl. In anotherembodiment is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt thereof, wherein R⁵ is phenyl substituted with 1 or 2R¹⁴, and R⁶ is phenyl substituted with 1 or 2 R¹⁴. In another embodimentis a compound of Formula (Ia), or a pharmaceutically acceptable saltthereof, wherein R⁵ is unsubstituted —C₁₋₈alkyl-C₆₋₁₀aryl, and R⁶ isunsubstituted —C₁₋₈alkyl-C₆₋₁₀aryl. In another embodiment is a compoundof Formula (Ia), or a pharmaceutically acceptable salt thereof, whereinR⁵ is —C₁₋₈alkyl-C₆₋₁₀aryl substituted with 1 or 2 R¹⁴, and R⁶ is—C₁₋₈alkyl-C₆₋₁₀aryl substituted with 1 or 2 R¹⁴. In another embodimentis a compound of Formula (Ia), or a pharmaceutically acceptable saltthereof, wherein R⁵ is unsubstituted —CH₂— phenyl, and R⁶ isunsubstituted —CH₂-phenyl. In another embodiment is a compound ofFormula (Ia), or a pharmaceutically acceptable salt thereof, wherein R⁵is —CH₂-phenyl substituted with 1 or 2 R¹⁴, and R⁶ is —CH₂-phenylsubstituted with 1 or 2 R¹⁴. In another embodiment is a compound ofFormula (Ia), or a pharmaceutically acceptable salt thereof, wherein R⁵is unsubstituted C₂₋₉heteroaryl, and R⁶ is unsubstituted C₂₋₉heteroaryl.In another embodiment is a compound of Formula (Ia), or apharmaceutically acceptable salt thereof, wherein R⁵ is C₂₋₉heteroarylsubstituted with 1 or 2 R¹⁴, and R⁶ is C₂₋₉heteroaryl substituted with 1or 2 R¹⁴. In another embodiment is a compound of Formula (Ia), or apharmaceutically acceptable salt thereof, wherein R⁵ is unsubstituted—C₁₋₈alkyl-C₂₋₉heteroaryl, and R⁶ is unsubstituted—C₁₋₈alkyl-C₂₋₉heteroaryl. In another embodiment is a compound ofFormula (Ia), or a pharmaceutically acceptable salt thereof, wherein R⁵is —C₁₋₈alkyl-C₂₋₉heteroaryl substituted with 1 or 2 R¹⁰, and R⁶ is—C₁₋₈alkyl-C₂₋₉heteroaryl substituted with 1 or 2 R¹⁴.

In another embodiment is a compound of Formula (Ia), or apharmaceutically acceptable salt thereof, wherein R⁵ is H and R⁶ isC₃₋₁₈alkyl. In another embodiment is a compound of Formula (Ia), or apharmaceutically acceptable salt thereof, wherein R⁵ is H and R⁶ isC₆₋₁₅alkyl. In another embodiment is a compound of Formula (Ia), or apharmaceutically acceptable salt thereof, wherein R⁵ is H and R⁶ isC₆₋₁₀alkyl. In another embodiment is a compound of Formula (Ia), or apharmaceutically acceptable salt thereof, wherein R⁵ is H and R⁶ isC₃₋₁₈alkenyl. In another embodiment is a compound of Formula (Ia), or apharmaceutically acceptable salt thereof, wherein R⁵ is H and R⁶ isC₆₋₁₅alkenyl. In another embodiment is a compound of Formula (Ia), or apharmaceutically acceptable salt thereof, wherein R⁵ is H and R⁶ isC₆₋₁₀alkenyl. In another embodiment is a compound of Formula (Ia), or apharmaceutically acceptable salt thereof, wherein R⁵ is H and R⁶ isC₃₋₁₈alkynyl. In another embodiment is a compound of Formula (Ia), or apharmaceutically acceptable salt thereof, wherein R⁵ is H and R⁶ isC₆₋₁₅alkynyl. In another embodiment is a compound of Formula (Ia), or apharmaceutically acceptable salt thereof, wherein R⁵ is H and R⁶ isC₆₋₁₀alkynyl. In another embodiment is a compound of Formula (Ia), or apharmaceutically acceptable salt thereof, wherein R⁵ is H and R⁶ isC₃₋₁₈haloalkyl. In another embodiment is a compound of Formula (Ia), ora pharmaceutically acceptable salt thereof, wherein R⁵ is H and R⁶ isC₆₋₁₅haloalkyl. In another embodiment is a compound of Formula (Ia), ora pharmaceutically acceptable salt thereof, wherein R⁵ is H and R⁶ isC₆₋₁₀haloalkyl. In another embodiment is a compound of Formula (Ia), ora pharmaceutically acceptable salt thereof, wherein R⁵ is H and R⁶ is—C₁₋₄alkyl-OC(O)C₁₋₈alkyl. In another embodiment is a compound ofFormula (Ia), or a pharmaceutically acceptable salt thereof, wherein R⁵is H and R⁶ is —C₁₋₂alkyl-OC(O)C₁₋₈alkyl. In another embodiment is acompound of Formula (Ia), or a pharmaceutically acceptable salt thereof,wherein R⁵ is H and R⁶ is —CH₂OC(O)C₁₋₈alkyl. In another embodiment is acompound of Formula (Ia), or a pharmaceutically acceptable salt thereof,wherein R⁵ is H and R⁶ is —C₁₋₄alkyl-OC(O)C₁₋₄alkyl. In anotherembodiment is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt thereof, wherein R⁵ is H and R⁶ is—C₁₋₂alkyl-OC(O)C₁₋₄alkyl. In another embodiment is a compound ofFormula (Ia), or a pharmaceutically acceptable salt thereof, wherein R⁵is H and R⁶ is —CH₂OC(O)C₁₋₄alkyl. In another embodiment is a compoundof Formula (Ia), or a pharmaceutically acceptable salt thereof, whereinR⁵ is H and R⁶ is —C₁₋₄alkyl-OC(O)C(CH₃)₃. In another embodiment is acompound of Formula (Ia), or a pharmaceutically acceptable salt thereof,wherein R⁵ is H and R⁶ is —C₁₋₂alkyl-OC(O)C(CH₃)₃. In another embodimentis a compound of Formula (Ia), or a pharmaceutically acceptable saltthereof, wherein R⁵ is H and R⁶ is —CH₂OC(O)C(CH₃)₃.

In another embodiment is a compound of Formula (Ia), or apharmaceutically acceptable salt thereof, wherein R⁸ is C₃₋₁₈alkyl. Inanother embodiment is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₃₋₁₂alkyl. In another embodimentis a compound of Formula (Ia), or a pharmaceutically acceptable saltthereof, wherein R⁸ is C₆₋₁₂alkyl. In another embodiment is a compoundof Formula (Ia), or a pharmaceutically acceptable salt thereof, whereinR⁸ is C₆₋₁₀alkyl. In another embodiment is a compound of Formula (Ia),or a pharmaceutically acceptable salt thereof, wherein R⁸ is C₈₋₁₀alkyl.In another embodiment is a compound of Formula (Ia), or apharmaceutically acceptable salt thereof, wherein R⁸ is —(CH₂)₂CH₃. Inanother embodiment is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is —(CH₂)₃CH₃. In another embodimentis a compound of Formula (Ia), or a pharmaceutically acceptable saltthereof, wherein R⁸ is —(CH₂)₄CH₃. In another embodiment is a compoundof Formula (Ia), or a pharmaceutically acceptable salt thereof, whereinR⁸ is —(CH₂)₅CH₃. In another embodiment is a compound of Formula (Ia),or a pharmaceutically acceptable salt thereof, wherein R⁸ is —(CH₂)₆CH₃.In another embodiment is a compound of Formula (Ia), or apharmaceutically acceptable salt thereof, wherein R⁸ is —(CH₂)₇CH₃. Inanother embodiment is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is —(CH₂)₈CH₃. In another embodimentis a compound of Formula (Ia), or a pharmaceutically acceptable saltthereof, wherein R⁸ is —(CH₂)₉CH₃. In another embodiment is a compoundof Formula (Ia), or a pharmaceutically acceptable salt thereof, whereinR⁸ is —(CH₂)₁₀CH₃. In another embodiment is a compound of Formula (Ia),or a pharmaceutically acceptable salt thereof, wherein R⁸ is—(CH₂)₁₁CH₃. In another embodiment is a compound of Formula (Ia), or apharmaceutically acceptable salt thereof, wherein R⁸ is —(CH₂)₁₂CH₃. Inanother embodiment is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is —(CH₂)₁₃CH₃. In anotherembodiment is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is —(CH₂)₁₄CH₃. In anotherembodiment is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is —(CH₂)₁₅CH₃. In anotherembodiment is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is —(CH₂)₁₆CH₃. In anotherembodiment is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is —(CH₂)₁₇CH₃. In anotherembodiment is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₃₋₁₈alkenyl. In anotherembodiment is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₃₋₁₂alkenyl. In anotherembodiment is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₆₋₁₂alkenyl. In anotherembodiment is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₆₋₁₀alkenyl. In anotherembodiment is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₈₋₁₀alkenyl. In anotherembodiment is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₃₋₁₈alkynyl. In anotherembodiment is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₃₋₁₂alkynyl. In anotherembodiment is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₆₋₁₂alkynyl. In anotherembodiment is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₆₋₁₀alkynyl. In anotherembodiment is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₈₋₁₀alkynyl. In anotherembodiment is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₃₋₁₈haloalkyl. In anotherembodiment is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₃₋₁₂haloalkyl. In anotherembodiment is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₆₋₁₂haloalkyl. In anotherembodiment is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₆₋₁₀haloalkyl. In anotherembodiment is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₈₋₁₀haloalkyl. In anotherembodiment is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₃₋₈cycloalkyl. In anotherembodiment is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₃₋₆cycloalkyl. In anotherembodiment is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₆₋₁₀aryl optionally substitutedwith 1, 2, 3, or 4 R¹⁴. In another embodiment is a compound of Formula(Ia), or a pharmaceutically acceptable salt thereof, wherein R⁸ isunsubstituted C₆₋₁₀aryl. In another embodiment is a compound of Formula(Ia), or a pharmaceutically acceptable salt thereof, wherein R⁸ isC₆₋₁₀aryl substituted with 1 or 2 R¹⁴. In another embodiment is acompound of Formula (Ia), or a pharmaceutically acceptable salt thereof,wherein R⁸ is phenyl optionally substituted with 1, 2, 3, or 4 R¹⁴. Inanother embodiment is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is unsubstituted phenyl. In anotherembodiment is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is phenyl substituted with 1 or 2R¹⁴. In another embodiment is a compound of Formula (Ia), or apharmaceutically acceptable salt thereof, wherein R⁸ is—C₁₋₈alkyl-C₆₋₁₀aryl optionally substituted with 1, 2, 3, or 4 R¹⁴. Inanother embodiment is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is unsubstituted—C₁₋₈alkyl-C₆₋₁₀aryl. In another embodiment is a compound of Formula(Ia), or a pharmaceutically acceptable salt thereof, wherein R⁸ is—C₁₋₈alkyl-C₆₋₁₀aryl substituted with 1 or 2 R¹⁴. In another embodimentis a compound of Formula (Ia), or a pharmaceutically acceptable saltthereof, wherein R⁸ is —CH₂-phenyl optionally substituted with 1, 2, 3,or 4 R¹⁴. In another embodiment is a compound of Formula (Ia), or apharmaceutically acceptable salt thereof, wherein R⁸ is unsubstituted—CH₂-phenyl. In another embodiment is a compound of Formula (Ia), or apharmaceutically acceptable salt thereof, wherein R⁸ is —CH₂-phenylsubstituted with 1 or 2 R¹⁴. In another embodiment is a compound ofFormula (Ia), or a pharmaceutically acceptable salt thereof, wherein R⁸is C₂₋₉heteroaryl optionally substituted with 1, 2, 3, or 4 R¹⁴. Inanother embodiment is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is unsubstituted C₂₋₉heteroaryl. Inanother embodiment is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₂₋₉heteroaryl substituted with 1or 2 R¹⁴. In another embodiment is a compound of Formula (Ia), or apharmaceutically acceptable salt thereof, wherein R⁸ is—CH₂—C₂₋₉heteroaryl optionally substituted with 1, 2, 3, or 4 R¹⁴. Inanother embodiment is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is unsubstituted—CH₂—C₂₋₉heteroaryl. In another embodiment is a compound of Formula(Ia), or a pharmaceutically acceptable salt thereof, wherein R⁸ is—CH₂—C₂₋₉heteroaryl substituted with 1 or 2 R¹⁴.

In another embodiment is a compound of Formula (Ia), or apharmaceutically acceptable salt thereof, wherein R³ is H, —C(O)R⁹, or—C(O)OR⁹. In another embodiment is a compound of Formula (Ia), or apharmaceutically acceptable salt thereof, wherein R³ is —C(O)R⁹. Inanother embodiment is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt thereof, wherein R³ is —C(O)R⁹ and R⁹ is C₁₋₁₀alkyl. Inanother embodiment is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt thereof, wherein R³ is —C(O)R⁹ and R⁹ is C₁₋₆alkyl. Inanother embodiment is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt thereof, wherein R³ is —C(O)R⁹ and R⁹ is C₁₋₄alkyl. Inanother embodiment is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt thereof, wherein R³ is —C(O)R⁹ and R⁹ is —CH₃. Inanother embodiment is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt thereof, wherein R³ is —C(O)R⁹ and R⁹ is —CH₂CH₃. Inanother embodiment is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt thereof, wherein R³ is —C(O)OR⁹. In another embodimentis a compound of Formula (Ia), or a pharmaceutically acceptable saltthereof, wherein R³ is —C(O)OR⁹ and R⁹ is C₁₋₁₀alkyl. In anotherembodiment is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt thereof, wherein R³ is —C(O)OR⁹ and R⁹ is C₁₋₆alkyl. Inanother embodiment is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt thereof, wherein R³ is —C(O)OR⁹ and R⁹ is C₁₋₄alkyl. Inanother embodiment is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt thereof, wherein R³ is —C(O)OR⁹ and R⁹ is —CH₃. Inanother embodiment is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt thereof, wherein R³ is —C(O)OR⁹ and R⁹ is —CH₂CH₃.

In some embodiments is a compound of Formula (I′) having the structureof Formula (Ib):

wherein:

-   -   R³ is H, —C(O)R⁹, or —C(O)OR⁹;    -   R⁸ is C₃₋₁₈alkyl, C₃₋₁₈alkenyl, C₃₋₁₈alkynyl, C₃₋₁₈haloalkyl,        C₃₋₈cycloalkyl, C₆₋₁₀aryl, —C₁₋₈alkyl-C₆₋₁₀aryl C₂₋₉heteroaryl,        or —C₁₋₈alkyl-C₂₋₉heteroaryl, wherein C₆₋₁₀aryl,        —C₁₋₈alkyl-C₆₋₁₀aryl C₂₋₉heteroaryl, or        —C₁₋₈alkyl-C₂₋₉heteroaryl are optionally substituted with 1, 2,        3, or 4 R¹⁴;    -   R⁹ is C₁₋₁₂alkyl;    -   R¹⁰ and R¹¹ are each independently H or C₁₋₁₂alkyl; or R¹⁰ and        R¹¹ form a 5- or 6-membered cycloalkyl ring or a 5- or        6-membered heterocycloalkyl ring, wherein the 5- or 6-membered        cycloalkyl ring or the 5- or 6-membered heterocycloalkyl ring        are optionally substituted with one or two R¹³;    -   R¹² is H or C₁₋₁₂alkyl;    -   each R¹³ is independently selected from C₁₋₁₂alkyl;    -   each R¹⁴ is independently selected from halogen, C₁₋₈alkyl,        C₁₋₈haloalkyl, C₁₋₈alkoxy, and —C(O)R¹³; and    -   m is 0 or 1;    -   or a pharmaceutically acceptable salt thereof.

In another embodiment is a compound of Formula (Ib), or apharmaceutically acceptable salt thereof, wherein m is 1. In anotherembodiment is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt thereof, wherein m is 1 and R¹⁰, R¹¹ and R¹² are each H.In another embodiment is a compound of Formula (Ib), or apharmaceutically acceptable salt thereof, wherein m is 1 and R¹⁰, R¹¹and R¹² are each C₁₋₁₂alkyl. In another embodiment is a compound ofFormula (Ib), or a pharmaceutically acceptable salt thereof, wherein mis 1 and R¹⁰, R¹¹ and R¹² are each C₁₋₄alkyl. In another embodiment is acompound of Formula (Ib), or a pharmaceutically acceptable salt thereof,wherein m is 1 and R¹⁰, R¹¹ and R¹² are each —CH₃. In another embodimentis a compound of Formula (Ib), or a pharmaceutically acceptable saltthereof, wherein m is 1, R¹⁰ is C₁₋₁₂alkyl, and R¹¹ and R¹² are each H.In another embodiment is a compound of Formula (Ib), or apharmaceutically acceptable salt thereof, wherein m is 1, R¹⁰ isC₁₋₄alkyl, and R¹¹ and R¹² are each H. In another embodiment is acompound of Formula (Ib), or a pharmaceutically acceptable salt thereof,wherein m is 1, R¹⁰ is —CH₃, and R¹¹ and R¹² are each H. In anotherembodiment is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt thereof, wherein m is 1, R¹¹ is C₁₋₁₂alkyl, and R¹⁰ andR¹² are each H. In another embodiment is a compound of Formula (Ib), ora pharmaceutically acceptable salt thereof, wherein m is 1, R¹¹ isC₁₋₄alkyl, and R¹⁰ and R¹² are each H. In another embodiment is acompound of Formula (Ib), or a pharmaceutically acceptable salt thereof,wherein m is 1, R¹¹ is —CH₃, and R¹⁰ and R¹² are each H. In anotherembodiment is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt thereof, wherein m is 1, R¹⁰ is H, and R¹¹ and R¹² areeach C₁₋₁₂alkyl. In another embodiment is a compound of Formula (Ib), ora pharmaceutically acceptable salt thereof, wherein m is 1, R¹⁰ is H,and R¹¹ and R¹² are each C₁₋₄alkyl. In another embodiment is a compoundof Formula (Ib), or a pharmaceutically acceptable salt thereof, whereinm is 1, R¹⁰ is H, and R¹¹ and R¹² are each —CH₃. In another embodimentis a compound of Formula (Ib), or a pharmaceutically acceptable saltthereof, wherein m is 1, R¹¹ is H, and R¹⁰ and R¹² are each C₁₋₁₂alkyl.In another embodiment is a compound of Formula (Ib), or apharmaceutically acceptable salt thereof, wherein m is 1, R¹¹ is H, andR¹⁰ and R¹² are each C₁₋₄alkyl. In another embodiment is a compound ofFormula (Ib), or a pharmaceutically acceptable salt thereof, wherein mis 1, R¹¹ is H, and R¹⁰ and R¹² are each —CH₃. In another embodiment isa compound of Formula (Ib), or a pharmaceutically acceptable saltthereof, wherein m is 1, R¹² is H, and R¹⁰ and R¹¹ form a 5- or6-membered cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring,wherein the 5- or 6-membered cycloalkyl ring or the 5- or 6-memberedheterocycloalkyl ring are optionally substituted with one or two R¹³. Inanother embodiment is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt thereof, wherein m is 1, R¹² is H, and R¹⁰ and R¹¹ forma 5- or 6-membered cycloalkyl ring optionally substituted with one ortwo R¹³. In another embodiment is a compound of Formula (Ib), or apharmaceutically acceptable salt thereof, wherein m is 1, R¹² is H, andR¹⁰ and R¹¹ form a 5- or 6-membered heterocycloalkyl ring optionallysubstituted with one or two R¹³. In another embodiment is a compound ofFormula (Ib), or a pharmaceutically acceptable salt thereof, wherein mis 1, R¹² is C₁₋₁₂alkyl, and R¹⁰ and R¹¹ form a 5- or 6-memberedcycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring, wherein the5- or 6-membered cycloalkyl ring or the 5- or 6-memberedheterocycloalkyl ring are optionally substituted with one or two R¹³. Inanother embodiment is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt thereof, wherein m is 1, R¹² is C₁₋₁₂alkyl, and R¹⁰ andR¹¹ form a 5- or 6-membered cycloalkyl ring optionally substituted withone or two R¹³. In another embodiment is a compound of Formula (Ib), ora pharmaceutically acceptable salt thereof, wherein m is 1, R¹² isC₁₋₁₂alkyl, and R¹⁰ and R¹¹ form a 5- or 6-membered heterocycloalkylring optionally substituted with one or two R¹³. In another embodimentis a compound of Formula (Ib), or a pharmaceutically acceptable saltthereof, wherein m is 0. In another embodiment is a compound of Formula(Ib), or a pharmaceutically acceptable salt thereof, wherein m is 0 andR¹⁰ and R¹¹ are each H. In another embodiment is a compound of Formula(Ib), or a pharmaceutically acceptable salt thereof, wherein m is 0 andR¹⁰ and R¹¹ are each C₁₋₁₂alkyl. In another embodiment is a compound ofFormula (Ib), or a pharmaceutically acceptable salt thereof, wherein mis 0 and R¹⁰ and R¹¹ are each C₁₋₄alkyl. In another embodiment is acompound of Formula (Ib), or a pharmaceutically acceptable salt thereof,wherein m is 0 and R¹⁰ and R¹¹ are each —CH₃. In another embodiment is acompound of Formula (Ib), or a pharmaceutically acceptable salt thereof,wherein m is 0, R¹⁰ is H, and R¹¹ is C₁₋₁₂alkyl. In another embodimentis a compound of Formula (Ib), or a pharmaceutically acceptable saltthereof, wherein m is 0, R¹⁰ is H, and R¹¹ is C₁₋₄alkyl. In anotherembodiment is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt thereof, wherein m is 0, R¹⁰ is H, and R¹¹ is —CH₃. Inanother embodiment is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt thereof, wherein m is 0, R¹⁰ is C₁₋₁₂alkyl, and R¹¹ isH. In another embodiment is a compound of Formula (Ib), or apharmaceutically acceptable salt thereof, wherein m is 0, R¹⁰ isC₁₋₄alkyl, and R¹¹ is H. In another embodiment is a compound of Formula(Ib), or a pharmaceutically acceptable salt thereof, wherein m is 0, R¹⁰is —CH₃, and R¹¹ is H. In another embodiment is a compound of Formula(Ib), or a pharmaceutically acceptable salt thereof, wherein m is 0, andR¹⁰ and R¹¹ form a 5- or 6-membered cycloalkyl ring or a 5- or6-membered heterocycloalkyl ring, wherein the 5- or 6-memberedcycloalkyl ring or the 5- or 6-membered heterocycloalkyl ring areoptionally substituted with one or two R¹³. In another embodiment is acompound of Formula (Ib), or a pharmaceutically acceptable salt thereof,wherein m is 0, and R¹⁰ and R¹¹ form a 5- or 6-membered cycloalkyl ringoptionally substituted with one or two R¹³. In another embodiment is acompound of Formula (Ib), or a pharmaceutically acceptable salt thereof,wherein m is 0, and R¹⁰ and R¹¹ form a 5- or 6-membered heterocycloalkylring optionally substituted with one or two R¹³.

In another embodiment is a compound of Formula (Ib), or apharmaceutically acceptable salt thereof, wherein R⁸ is C₃₋₁₈alkyl. Inanother embodiment is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₃₋₁₂alkyl. In another embodimentis a compound of Formula (Ib), or a pharmaceutically acceptable saltthereof, wherein R⁸ is C₆₋₁₂alkyl. In another embodiment is a compoundof Formula (Ib), or a pharmaceutically acceptable salt thereof, whereinR⁸ is C₆₋₁₀alkyl. In another embodiment is a compound of Formula (Ib),or a pharmaceutically acceptable salt thereof, wherein R⁸ is C₈₋₁₀alkyl.In another embodiment is a compound of Formula (Ib), or apharmaceutically acceptable salt thereof, wherein R⁸ is —(CH₂)₂CH₃. Inanother embodiment is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is —(CH₂)₃CH₃. In another embodimentis a compound of Formula (Ib), or a pharmaceutically acceptable saltthereof, wherein R⁸ is —(CH₂)₄CH₃. In another embodiment is a compoundof Formula (Ib), or a pharmaceutically acceptable salt thereof, whereinR⁸ is —(CH₂)₅CH₃. In another embodiment is a compound of Formula (Ib),or a pharmaceutically acceptable salt thereof, wherein R⁸ is —(CH₂)₆CH₃.In another embodiment is a compound of Formula (Ib), or apharmaceutically acceptable salt thereof, wherein R⁸ is —(CH₂)₇CH₃. Inanother embodiment is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is —(CH₂)₈CH₃. In another embodimentis a compound of Formula (Ib), or a pharmaceutically acceptable saltthereof, wherein R⁸ is —(CH₂)₉CH₃. In another embodiment is a compoundof Formula (Ib), or a pharmaceutically acceptable salt thereof, whereinR⁸ is —(CH₂)₁₀CH₃. In another embodiment is a compound of Formula (Ib),or a pharmaceutically acceptable salt thereof, wherein R⁸ is—(CH₂)₁₁CH₃. In another embodiment is a compound of Formula (Ib), or apharmaceutically acceptable salt thereof, wherein R⁸ is —(CH₂)₁₂CH₃. Inanother embodiment is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is —(CH₂)₁₃CH₃. In anotherembodiment is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is —(CH₂)₁₄CH₃. In anotherembodiment is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is —(CH₂)₁₅CH₃. In anotherembodiment is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is —(CH₂)₁₆CH₃. In anotherembodiment is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is —(CH₂)₁₇CH₃. In anotherembodiment is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₃₋₁₈alkenyl. In anotherembodiment is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₃₋₁₂alkenyl. In anotherembodiment is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₆₋₁₂alkenyl. In anotherembodiment is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₆₋₁₀alkenyl. In anotherembodiment is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₈₋₁₀alkenyl. In anotherembodiment is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₃₋₁₈alkynyl. In anotherembodiment is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₃₋₁₂alkynyl. In anotherembodiment is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₆₋₁₂alkynyl. In anotherembodiment is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₆₋₁₀alkynyl. In anotherembodiment is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₈₋₁₀alkynyl. In anotherembodiment is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₃₋₁₈haloalkyl. In anotherembodiment is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₃₋₁₂haloalkyl. In anotherembodiment is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₆₋₁₂haloalkyl. In anotherembodiment is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₆₋₁₀haloalkyl. In anotherembodiment is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₈₋₁₀haloalkyl. In anotherembodiment is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₃₋₈cycloalkyl. In anotherembodiment is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₃₋₆cycloalkyl. In anotherembodiment is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₆₋₁₀aryl optionally substitutedwith 1, 2, 3, or 4 R¹⁴. In another embodiment is a compound of Formula(Ib), or a pharmaceutically acceptable salt thereof, wherein R⁸ isunsubstituted C₆₋₁₀aryl. In another embodiment is a compound of Formula(Ib), or a pharmaceutically acceptable salt thereof, wherein R⁸ isC₆₋₁₀aryl substituted with 1 or 2 R¹⁴. In another embodiment is acompound of Formula (Ib), or a pharmaceutically acceptable salt thereof,wherein R⁸ is phenyl optionally substituted with 1, 2, 3, or 4 R¹⁴. Inanother embodiment is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is unsubstituted phenyl. In anotherembodiment is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is phenyl substituted with 1 or 2R¹⁴. In another embodiment is a compound of Formula (Ib), or apharmaceutically acceptable salt thereof, wherein R⁸ is—C₁₋₈alkyl-C₆₋₁₀aryl optionally substituted with 1, 2, 3, or 4 R¹⁴. Inanother embodiment is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is unsubstituted—C₁₋₈alkyl-C₆₋₁₀aryl. In another embodiment is a compound of Formula(Ib), or a pharmaceutically acceptable salt thereof, wherein R⁸ is—C₁₋₈alkyl-C₆₋₁₀aryl substituted with 1 or 2 R¹⁴. In another embodimentis a compound of Formula (Ib), or a pharmaceutically acceptable saltthereof, wherein R⁸ is —CH₂-phenyl optionally substituted with 1, 2, 3,or 4 R¹⁴. In another embodiment is a compound of Formula (Ib), or apharmaceutically acceptable salt thereof, wherein R⁸ is unsubstituted—CH₂-phenyl. In another embodiment is a compound of Formula (Ib), or apharmaceutically acceptable salt thereof, wherein R⁸ is —CH₂-phenylsubstituted with 1 or 2 R¹⁴. In another embodiment is a compound ofFormula (Ib), or a pharmaceutically acceptable salt thereof, wherein R⁸is C₂₋₉heteroaryl optionally substituted with 1, 2, 3, or 4 R¹⁴. Inanother embodiment is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is unsubstituted C₂₋₉heteroaryl. Inanother embodiment is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₂₋₉heteroaryl substituted with 1or 2 R¹⁴. In another embodiment is a compound of Formula (Ib), or apharmaceutically acceptable salt thereof, wherein R⁸ is—CH₂—C₂₋₉heteroaryl optionally substituted with 1, 2, 3, or 4 R¹⁴. Inanother embodiment is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is unsubstituted—CH₂—C₂₋₉heteroaryl. In another embodiment is a compound of Formula(Ib), or a pharmaceutically acceptable salt thereof, wherein R⁸ is—CH₂—C₂₋₉heteroaryl substituted with 1 or 2 R¹⁴.

In another embodiment is a compound of Formula (Ib), or apharmaceutically acceptable salt thereof, wherein R³ is H. In anotherembodiment is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt thereof, wherein R³ is —C(O)R⁹. In another embodiment isa compound of Formula (Ib), or a pharmaceutically acceptable saltthereof, wherein R³ is —C(O)R⁹ and R⁹ is C₁₋₁₀alkyl. In anotherembodiment is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt thereof, wherein R³ is —C(O)R⁹ and R⁹ is C₁₋₆alkyl. Inanother embodiment is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt thereof, wherein R³ is —C(O)R⁹ and R⁹ is C₁₋₄alkyl. Inanother embodiment is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt thereof, wherein R³ is —C(O)R⁹ and R⁹ is —CH₃. Inanother embodiment is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt thereof, wherein R³ is —C(O)R⁹ and R⁹ is —CH₂CH₃. Inanother embodiment is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt thereof, wherein R³ is —C(O)OR⁹. In another embodimentis a compound of Formula (Ib), or a pharmaceutically acceptable saltthereof, wherein R³ is —C(O)OR⁹ and R⁹ is C₁₋₁₀alkyl. In anotherembodiment is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt thereof, wherein R³ is —C(O)OR⁹ and R⁹ is C₁₋₆alkyl. Inanother embodiment is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt thereof, wherein R³ is —C(O)OR⁹ and R⁹ is C₁₋₄alkyl. Inanother embodiment is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt thereof, wherein R³ is —C(O)OR⁹ and R⁹ is —CH₃. Inanother embodiment is a compound of Formula (Ib), or a pharmaceuticallyacceptable salt thereof, wherein R³ is —C(O)OR⁹ and R⁹ is —CH₂CH₃.

In some embodiments is a compound of Formula (I′) having the structureof Formula (Ic):

wherein:

-   -   R³ is H, —C(O)R⁹, or —C(O)OR⁹;    -   each R⁷ is independently selected from halogen, C₁₋₈alkyl,        C₁₋₈haloalkyl, and C₁₋₈alkoxy;    -   R⁸ is C₃₋₁₈alkyl, C₃₋₁₈alkenyl, C₃₋₁₈alkynyl, C₃₋₁₈haloalkyl,        C₃₋₈cycloalkyl, C₆₋₁₀aryl, —C₁₋₈alkyl-C₆₋₁₀aryl, C₂₋₉heteroaryl,        or —C₁₋₈alkyl-C₂₋₉heteroaryl, wherein C₆₋₁₀aryl,        —C₁₋₈alkyl-C₆₋₁₀aryl, C₂₋₉heteroaryl, or        —C₁₋₈alkyl-C₂₋₉heteroaryl are optionally substituted with 1, 2,        3, or 4 R¹⁴;    -   R⁹ is C₁₋₁₂alkyl;    -   each R¹³ is independently selected from C₁₋₁₂alkyl;    -   each R¹⁴ is independently selected from halogen, C₁₋₈alkyl,        C₁₋₈haloalkyl, C₁₋₈alkoxy, and —C(O)R¹³;    -   n is 0, 1, 2, 3, or 4; and    -   p is 0 or 1;    -   or a pharmaceutically acceptable salt thereof.

In another embodiment is a compound of Formula (Ic), or apharmaceutically acceptable salt thereof, wherein p is 1. In anotherembodiment is a compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof, wherein p is 1 and n is 0. In anotherembodiment is a compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof, wherein p is 1 and n is 1, 2, 3, or 4. Inanother embodiment is a compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof, wherein p is 1, n is 1, 2, 3, or 4, and each R⁷is independently selected from C₁₋₈alkyl, C₁₋₈haloalkyl, and C₁₋₈alkoxy.In another embodiment is a compound of Formula (Ic), or apharmaceutically acceptable salt thereof, wherein p is 1 and n is 1 or2. In another embodiment is a compound of Formula (Ic), or apharmaceutically acceptable salt thereof, wherein p is 1, n is 1 or 2,and each R⁷ is independently selected from C₁₋₈alkyl, C₁₋₈haloalkyl, andC₁₋₈alkoxy. In another embodiment is a compound of Formula (Ic), or apharmaceutically acceptable salt thereof, wherein p is 1, n is 2. Inanother embodiment is a compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof, wherein p is 1, n is 2, and each R⁷ isindependently selected from C₁₋₈alkyl, C₁₋₈haloalkyl, and C₁₋₈alkoxy. Inanother embodiment is a compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof, wherein p is 1 and n is 1. In anotherembodiment is a compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof, wherein p is 1, n is 1, and R⁷ is selected fromC₁₋₈alkyl, C₁₋₈haloalkyl, and C₁₋₈alkoxy. In another embodiment is acompound of Formula (Ic), or a pharmaceutically acceptable salt thereof,wherein p is 1, n is 1, and R⁷ is halogen. In another embodiment is acompound of Formula (Ic), or a pharmaceutically acceptable salt thereof,wherein p is 1, n is 1, and R⁷ is C₁₋₈alkyl. In another embodiment is acompound of Formula (Ic), or a pharmaceutically acceptable salt thereof,wherein p is 1, n is 1, and R⁷ is C₁₋₈haloalkyl. In another embodimentis a compound of Formula (Ic), or a pharmaceutically acceptable saltthereof, wherein p is 1, n is 1, and R⁷ is C₁₋₈alkoxy. In anotherembodiment is a compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof, wherein p is 0. In another embodiment is acompound of Formula (Ic), or a pharmaceutically acceptable salt thereof,wherein p is 0 and n is 0. In another embodiment is a compound ofFormula (Ic), or a pharmaceutically acceptable salt thereof, wherein pis 0 and n is 1, 2, 3, or 4. In another embodiment is a compound ofFormula (Ic), or a pharmaceutically acceptable salt thereof, wherein pis 0, n is 1, 2, 3, or 4, and each R⁷ is independently selected fromC₁₋₈alkyl, C₁₋₈haloalkyl, and C₁₋₈alkoxy. In another embodiment is acompound of Formula (Ic), or a pharmaceutically acceptable salt thereof,wherein p is 0 and n is 1 or 2. In another embodiment is a compound ofFormula (Ic), or a pharmaceutically acceptable salt thereof, wherein pis 0, n is 1 or 2, and each R⁷ is independently selected from C₁₋₈alkyl,C₁₋₈haloalkyl, and C₁₋₈alkoxy. In another embodiment is a compound ofFormula (Ic), or a pharmaceutically acceptable salt thereof, wherein pis 0, n is 2. In another embodiment is a compound of Formula (Ic), or apharmaceutically acceptable salt thereof, wherein p is 0, n is 2, andeach R⁷ is independently selected from C₁₋₈alkyl, C₁₋₈haloalkyl, andC₁₋₈alkoxy. In another embodiment is a compound of Formula (Ic), or apharmaceutically acceptable salt thereof, wherein p is 0 and n is 1. Inanother embodiment is a compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof, wherein p is 0, n is 1, and R⁷ is selected fromC₁₋₈alkyl, C₁₋₈haloalkyl, and C₁₋₈alkoxy. In another embodiment is acompound of Formula (Ic), or a pharmaceutically acceptable salt thereof,wherein p is 0, n is 1, and R⁷ is halogen. In another embodiment is acompound of Formula (Ic), or a pharmaceutically acceptable salt thereof,wherein p is 0, n is 1, and R⁷ is C₁₋₈alkyl. In another embodiment is acompound of Formula (Ic), or a pharmaceutically acceptable salt thereof,wherein p is 0, n is 1, and R⁷ is C₁₋₈haloalkyl. In another embodimentis a compound of Formula (Ic), or a pharmaceutically acceptable saltthereof, wherein p is 0, n is 1, and R⁷ is C₁₋₈alkoxy.

In another embodiment is a compound of Formula (Ic), or apharmaceutically acceptable salt thereof, wherein R⁸ is C₃₋₁₈alkyl. Inanother embodiment is a compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₃₋₁₂alkyl. In another embodimentis a compound of Formula (Ic), or a pharmaceutically acceptable saltthereof, wherein R⁸ is C₆₋₁₂alkyl. In another embodiment is a compoundof Formula (Ic), or a pharmaceutically acceptable salt thereof, whereinR⁸ is C₆₋₁₀alkyl. In another embodiment is a compound of Formula (Ic),or a pharmaceutically acceptable salt thereof, wherein R⁸ is C₈₋₁₀alkyl.In another embodiment is a compound of Formula (Ic), or apharmaceutically acceptable salt thereof, wherein R⁸ is —(CH₂)₂CH₃. Inanother embodiment is a compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is —(CH₂)₃CH₃. In another embodimentis a compound of Formula (Ic), or a pharmaceutically acceptable saltthereof, wherein R⁸ is —(CH₂)₄CH₃. In another embodiment is a compoundof Formula (Ic), or a pharmaceutically acceptable salt thereof, whereinR⁸ is —(CH₂)₅CH₃. In another embodiment is a compound of Formula (Ic),or a pharmaceutically acceptable salt thereof, wherein R⁸ is —(CH₂)₆CH₃.In another embodiment is a compound of Formula (Ic), or apharmaceutically acceptable salt thereof, wherein R⁸ is —(CH₂)₇CH₃. Inanother embodiment is a compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is —(CH₂)₈CH₃. In another embodimentis a compound of Formula (Ic), or a pharmaceutically acceptable saltthereof, wherein R⁸ is —(CH₂)₉CH₃. In another embodiment is a compoundof Formula (Ic), or a pharmaceutically acceptable salt thereof, whereinR⁸ is —(CH₂)₁₀CH₃. In another embodiment is a compound of Formula (Ic),or a pharmaceutically acceptable salt thereof, wherein R⁸ is—(CH₂)₁₁CH₃. In another embodiment is a compound of Formula (Ic), or apharmaceutically acceptable salt thereof, wherein R⁸ is —(CH₂)₁₂CH₃. Inanother embodiment is a compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is —(CH₂)₁₃CH₃. In anotherembodiment is a compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is —(CH₂)₁₄CH₃. In anotherembodiment is a compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is —(CH₂)₁₅CH₃. In anotherembodiment is a compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is —(CH₂)₁₆CH₃. In anotherembodiment is a compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is —(CH₂)₁₇CH₃. In anotherembodiment is a compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₃₋₁₈alkenyl. In anotherembodiment is a compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₃₋₁₂alkenyl. In anotherembodiment is a compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₆₋₁₂alkenyl. In anotherembodiment is a compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₆₋₁₀alkenyl. In anotherembodiment is a compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₈₋₁₀alkenyl. In anotherembodiment is a compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₃₋₁₈alkynyl. In anotherembodiment is a compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₃₋₁₂alkynyl. In anotherembodiment is a compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₆₋₁₂alkynyl. In anotherembodiment is a compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₆₋₁₀alkynyl. In anotherembodiment is a compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₈₋₁₀alkynyl. In anotherembodiment is a compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₃₋₁₈haloalkyl. In anotherembodiment is a compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₃₋₁₂haloalkyl. In anotherembodiment is a compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₆₋₁₂haloalkyl. In anotherembodiment is a compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₆₋₁₀haloalkyl. In anotherembodiment is a compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₈₋₁₀haloalkyl. In anotherembodiment is a compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₃₋₈cycloalkyl. In anotherembodiment is a compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₃₋₆cycloalkyl. In anotherembodiment is a compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₆₋₁₀aryl optionally substitutedwith 1, 2, 3, or 4 R¹⁴. In another embodiment is a compound of Formula(Ic), or a pharmaceutically acceptable salt thereof, wherein R⁸ isunsubstituted C₆₋₁₀aryl. In another embodiment is a compound of Formula(Ic), or a pharmaceutically acceptable salt thereof, wherein R⁸ isC₆₋₁₀aryl substituted with 1 or 2 R¹⁴. In another embodiment is acompound of Formula (Ic), or a pharmaceutically acceptable salt thereof,wherein R⁸ is phenyl optionally substituted with 1, 2, 3, or 4 R¹⁴. Inanother embodiment is a compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is unsubstituted phenyl. In anotherembodiment is a compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is phenyl substituted with 1 or 2R¹⁴. In another embodiment is a compound of Formula (Ic), or apharmaceutically acceptable salt thereof, wherein R⁸ is—C₁₋₈alkyl-C₆₋₁₀aryl optionally substituted with 1, 2, 3, or 4 R¹⁴. Inanother embodiment is a compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is unsubstituted—C₁₋₈alkyl-C₆₋₁₀aryl. In another embodiment is a compound of Formula(Ic), or a pharmaceutically acceptable salt thereof, wherein R⁸ is—C₁₋₈alkyl-C₆₋₁₀aryl substituted with 1 or 2 R¹⁴. In another embodimentis a compound of Formula (Ic), or a pharmaceutically acceptable saltthereof, wherein R⁸ is —CH₂-phenyl optionally substituted with 1, 2, 3,or 4 R¹⁴. In another embodiment is a compound of Formula (Ic), or apharmaceutically acceptable salt thereof, wherein R⁸ is unsubstituted—CH₂— phenyl. In another embodiment is a compound of Formula (Ic), or apharmaceutically acceptable salt thereof, wherein R⁸ is —CH₂-phenylsubstituted with 1 or 2 R¹⁴. In another embodiment is a compound ofFormula (Ic), or a pharmaceutically acceptable salt thereof, wherein R⁸is C₂₋₉heteroaryl optionally substituted with 1, 2, 3, or 4 R¹⁴. Inanother embodiment is a compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is unsubstituted C₂₋₉heteroaryl. Inanother embodiment is a compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is C₂₋₉heteroaryl substituted with 1or 2 R¹⁴. In another embodiment is a compound of Formula (Ic), or apharmaceutically acceptable salt thereof, wherein R⁸ is—CH₂—C₂₋₉heteroaryl optionally substituted with 1, 2, 3, or 4 R¹⁴. Inanother embodiment is a compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is unsubstituted—CH₂—C₂₋₉heteroaryl. In another embodiment is a compound of Formula(Ic), or a pharmaceutically acceptable salt thereof, wherein R⁸ is—CH₂—C₂₋₉heteroaryl substituted with 1 or 2 R¹⁴.

In another embodiment is a compound of Formula (Ic), or apharmaceutically acceptable salt thereof, wherein R³ is H. In anotherembodiment is a compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof, wherein R³ is —C(O)R⁹. In another embodiment isa compound of Formula (Ic), or a pharmaceutically acceptable saltthereof, wherein R³ is —C(O)R⁹ and R⁹ is C₁₋₁₀alkyl. In anotherembodiment is a compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof, wherein R³ is —C(O)R⁹ and R⁹ is C₁₋₆alkyl. Inanother embodiment is a compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof, wherein R³ is —C(O)R⁹ and R⁹ is C₁₋₄alkyl. Inanother embodiment is a compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof, wherein R³ is —C(O)R⁹ and R⁹ is —CH₃. Inanother embodiment is a compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof, wherein R³ is —C(O)R⁹ and R⁹ is —CH₂CH₃. Inanother embodiment is a compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof, wherein R³ is —C(O)OR⁹. In another embodimentis a compound of Formula (Ic), or a pharmaceutically acceptable saltthereof, wherein R³ is —C(O)OR⁹ and R⁹ is C₁₋₁₀alkyl. In anotherembodiment is a compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof, wherein R³ is —C(O)OR⁹ and R⁹ is C₁₋₆alkyl. Inanother embodiment is a compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof, wherein R³ is —C(O)OR⁹ and R⁹ is C₁₋₄alkyl. Inanother embodiment is a compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof, wherein R³ is —C(O)OR⁹ and R⁹ is —CH₃. Inanother embodiment is a compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof, wherein R³ is —C(O)OR⁹ and R⁹ is —CH₂CH₃.

In another embodiment is a compound of Formula (II):

wherein:

-   -   R³ is H, —C(O)R⁹, or —C(O)OR⁹;    -   R⁴ is H;    -   R⁹ is C₁₋₈alkyl;    -   R¹¹ is C₃₋₁₈alkyl, C₃₋₁₈alkenyl, C₃₋₁₈alkynyl, C₃₋₁₈haloalkyl,        —C₁₋₄alkyl-OC(O)C₁₋₈alkyl, C₆₋₁₀aryl, —C₁₋₈alkyl-C₆₋₁₀aryl,        C₂₋₉heteroaryl, or —C₁₋₈alkyl-C₂₋₉heteroaryl, wherein C₆₋₁₀aryl,        —C₁₋₈alkyl-C₆₋₁₀aryl, C₂₋₉heteroaryl, or        —C₁₋₈alkyl-C₂₋₉heteroaryl are optionally substituted with 1, 2,        3, or 4 R¹²;    -   each R¹² is independently selected from halogen, C₁₋₈alkyl,        C₁₋₈haloalkyl, C₁₋₈alkoxy, and —C(O)R¹³; and    -   each R¹³ is independently selected from C₁₋₁₂alkyl;    -   or a pharmaceutically acceptable salt thereof.

In another embodiment is a compound of Formula (II), or apharmaceutically acceptable salt thereof, wherein R¹¹ is C₃₋₁₈alkyl. Inanother embodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is C₃₋₁₂alkyl. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is C₆₋₁₂alkyl. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is C₆₋₁₀alkyl. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is C₈₋₁₀alkyl. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is —(CH₂)₂CH₃. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is —(CH₂)₃CH₃. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is —(CH₂)₄CH₃. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is —(CH₂)₅CH₃. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is —(CH₂)₆CH₃. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is —(CH₂)₇CH₃. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is —(CH₂)₈CH₃. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is —(CH₂)₉CH₃. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is —(CH₂)₁₀CH₃. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is —(CH₂)₁₁CH₃. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is —(CH₂)₁₂CH₃. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is —(CH₂)₁₃CH₃. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is —(CH₂)₁₄CH₃. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is —(CH₂)₁₅CH₃. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is —(CH₂)₁₆CH₃. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is —(CH₂)₁₇CH₃. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is C₃₋₁₈alkenyl. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is C₃₋₁₂alkenyl. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is C₆₋₁₂alkenyl. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is C₆₋₁₀alkenyl. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is C₈₋₁₀alkenyl. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is C₃₋₁₈alkynyl. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is C₃₋₁₂alkynyl. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is C₆₋₁₂alkynyl. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is C₆₋₁₀alkynyl. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is C₈₋₁₀alkynyl. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is C₃₋₁₈haloalkyl. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is C₃₋₁₂haloalkyl. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is C₆₋₁₂haloalkyl. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is C₆₋₁₀haloalkyl. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is C₈₋₁₀haloalkyl. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is —C₁₋₄alkyl-OC(O)C₁₋₈alkyl. Inanother embodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is —C₁₋₂alkyl-OC(O)C₁₋₈alkyl. Inanother embodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is —CH₂OC(O)C₁₋₈alkyl. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is —C₁₋₄alkyl-OC(O)C₁₋₆alkyl. Inanother embodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is —C₁₋₂alkyl-OC(O)C₁₋₆alkyl. Inanother embodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is —CH₂OC(O)C₁₋₆alkyl. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is —C₁₋₄alkyl-OC(O)C₁₋₄alkyl. Inanother embodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is —C₁₋₂alkyl-OC(O)C₁₋₄alkyl. Inanother embodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is —CH₂OC(O)C₁₋₄alkyl. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is —C₁₋₄alkyl-OC(O)C(CH₃)₃. Inanother embodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is —C₁₋₂alkyl-OC(O)C(CH₃)₃. Inanother embodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is —CH₂OC(O)C(CH₃)₃. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is C₆₋₁₀aryl optionally substitutedwith 1, 2, 3, or 4 R¹². In another embodiment is a compound of Formula(II), or a pharmaceutically acceptable salt thereof, wherein R¹¹ isunsubstituted C₆₋₁₀aryl. In another embodiment is a compound of Formula(II), or a pharmaceutically acceptable salt thereof, wherein R¹¹ isC₆₋₁₀aryl substituted with 1, 2, 3, or 4 R¹². In another embodiment is acompound of Formula (II), or a pharmaceutically acceptable salt thereof,wherein R¹¹ is C₆₋₁₀aryl substituted with 1, 2, or 3 R¹². In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is C₆₋₁₀aryl substituted with 1 or2 In another embodiment is a compound of Formula (II), or apharmaceutically acceptable salt thereof, wherein R¹¹ is C₆₋₁₀arylsubstituted with 1 or 2 R¹² and each R¹² is independently selected fromhalogen, C₁₋₈alkyl, C₁₋₈haloalkyl, and C₁₋₈alkoxy. In another embodimentis a compound of Formula (II), or a pharmaceutically acceptable saltthereof, wherein R¹¹ is C₆₋₁₀aryl substituted with 1 or 2 R¹² and eachR¹² is independently selected from C₁₋₈alkyl, C₁₋₈alkoxy, and —C(O)R¹³.In another embodiment is a compound of Formula (II), or apharmaceutically acceptable salt thereof, wherein R¹¹ is C₆₋₁₀arylsubstituted with 1 or 2 R¹² and each R¹² is independently selected fromC₁₋₈alkyl, C₁₋₈haloalkyl, and C₁₋₈alkoxy. In another embodiment is acompound of Formula (II), or a pharmaceutically acceptable salt thereof,wherein R¹¹ is C₆₋₁₀aryl substituted with 1 or 2 R¹² and each R¹² isindependently selected from C₁₋₈alkyl and C₁₋₈alkoxy. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is C₆₋₁₀aryl substituted with 1 Inanother embodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is C₆₋₁₀aryl substituted with 1 R¹²and R¹² is selected from halogen, C₁₋₈alkyl, C₁₋₈haloalkyl, andC₁₋₈alkoxy. In another embodiment is a compound of Formula (II), or apharmaceutically acceptable salt thereof, wherein R¹¹ is C₆₋₁₀arylsubstituted with 1 R¹² and R¹² is selected from C₁₋₈alkyl, C₁₋₈alkoxy,and —C(O)R¹³. In another embodiment is a compound of Formula (II), or apharmaceutically acceptable salt thereof, wherein R¹¹ is C₆₋₁₀arylsubstituted with 1 R¹² and R¹² is selected from C₁₋₈alkyl andC₁₋₈alkoxy. In another embodiment is a compound of Formula (II), or apharmaceutically acceptable salt thereof, wherein R¹¹ is C₆₋₁₀arylsubstituted with 1 R¹² and R¹² is halogen. In another embodiment is acompound of Formula (II), or a pharmaceutically acceptable salt thereof,wherein R¹¹ is C₆₋₁₀aryl substituted with 1 R¹² and R¹² is —F. Inanother embodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is C₆₋₁₀aryl substituted with 1 R¹²and R¹² is —Cl. In another embodiment is a compound of Formula (II), ora pharmaceutically acceptable salt thereof, wherein R¹¹ is C₆₋₁₀arylsubstituted with 1 R¹² and R¹² is C₁₋₈alkyl. In another embodiment is acompound of Formula (II), or a pharmaceutically acceptable salt thereof,wherein R¹¹ is C₆₋₁₀aryl substituted with 1 R¹² and R¹² is —CH₃. Inanother embodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is C₆₋₁₀aryl substituted with 1 R¹²and R¹² is C₁₋₈haloalkyl. In another embodiment is a compound of Formula(II), or a pharmaceutically acceptable salt thereof, wherein R¹¹ isC₆₋₁₀aryl substituted with 1 R¹² and R¹² is —CF₃. In another embodimentis a compound of Formula (II), or a pharmaceutically acceptable saltthereof, wherein R¹¹ is C₆₋₁₀aryl substituted with 1 R¹² and R¹² isC₁₋₈alkoxy. In another embodiment is a compound of Formula (II), or apharmaceutically acceptable salt thereof, wherein R¹¹ is C₆₋₁₀arylsubstituted with 1 R¹² and R¹² is —OCH₃. In another embodiment is acompound of Formula (II), or a pharmaceutically acceptable salt thereof,wherein R¹¹ is C₆₋₁₀aryl substituted with 1 R¹² and R¹² is —C(O)R¹³. Inanother embodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is phenyl optionally substitutedwith 1, 2, 3, or 4 R¹². In another embodiment is a compound of Formula(II), or a pharmaceutically acceptable salt thereof, wherein R¹¹ isunsubstituted phenyl. In another embodiment is a compound of Formula(II), or a pharmaceutically acceptable salt thereof, wherein R¹¹ isphenyl substituted with 1, 2, 3, or 4 R¹². In another embodiment is acompound of Formula (II), or a pharmaceutically acceptable salt thereof,wherein R¹¹ is phenyl substituted with 1, 2, or 3 R¹². In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is phenyl substituted with 1 or 2R¹². In another embodiment is a compound of Formula (II), or apharmaceutically acceptable salt thereof, wherein R¹¹ is phenylsubstituted with 1 or 2 R¹² and each R¹² is independently selected fromhalogen, C₁₋₈alkyl, C₁₋₈haloalkyl, and C₁₋₈alkoxy. In another embodimentis a compound of Formula (II), or a pharmaceutically acceptable saltthereof, wherein R¹¹ is phenyl substituted with 1 or 2 R¹² and each R¹²is independently selected from C₁₋₈alkyl, C₁₋₈alkoxy, and —C(O)R¹³. Inanother embodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is phenyl substituted with 1 or 2R¹² and each R¹² is independently selected from C₁₋₈alkyl,C₁₋₈haloalkyl, and C₁₋₈alkoxy. In another embodiment is a compound ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein R¹¹is phenyl substituted with 1 or 2 R¹² and each R¹² is independentlyselected from C₁₋₈alkyl and C₁₋₈alkoxy. In another embodiment is acompound of Formula (II), or a pharmaceutically acceptable salt thereof,wherein R¹¹ is phenyl substituted with 1 R¹². In another embodiment is acompound of Formula (II), or a pharmaceutically acceptable salt thereof,wherein R¹¹ is phenyl substituted with 1 R¹² and R¹² is selected fromhalogen, C₁₋₈alkyl, C₁₋₈haloalkyl, and C₁₋₈alkoxy. In another embodimentis a compound of Formula (II), or a pharmaceutically acceptable saltthereof, wherein R¹¹ is phenyl substituted with 1 R¹² and R¹² isselected from C₁₋₈alkyl, C₁₋₈alkoxy, and —C(O)R¹³. In another embodimentis a compound of Formula (II), or a pharmaceutically acceptable saltthereof, wherein R¹¹ is phenyl substituted with 1 R¹² and R¹² isselected from C₁₋₈alkyl and C₁₋₈alkoxy. In another embodiment is acompound of Formula (II), or a pharmaceutically acceptable salt thereof,wherein R¹¹ is phenyl substituted with 1 R¹² and R¹² is halogen. Inanother embodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is phenyl substituted with 1 R¹²and R¹² is —F. In another embodiment is a compound of Formula (II), or apharmaceutically acceptable salt thereof, wherein R¹¹ is phenylsubstituted with 1 R¹² and R¹² is —Cl. In another embodiment is acompound of Formula (II), or a pharmaceutically acceptable salt thereof,wherein R¹¹ is phenyl substituted with 1 R¹² and R¹² is C₁₋₈alkyl. Inanother embodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is phenyl substituted with 1 R¹²and R¹² is —CH₃. In another embodiment is a compound of Formula (II), ora pharmaceutically acceptable salt thereof, wherein R¹¹ is phenylsubstituted with 1 R¹² and R¹² is C₁₋₈haloalkyl. In another embodimentis a compound of Formula (II), or a pharmaceutically acceptable saltthereof, wherein R¹¹ is phenyl substituted with 1 R¹² and R¹² is —CF₃.In another embodiment is a compound of Formula (II), or apharmaceutically acceptable salt thereof, wherein R¹¹ is phenylsubstituted with 1 R¹² and R¹² is C₁₋₈alkoxy. In another embodiment is acompound of Formula (II), or a pharmaceutically acceptable salt thereof,wherein R¹¹ is phenyl substituted with 1 R¹² and R¹² is —OCH₃. Inanother embodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is phenyl substituted with 1 R¹²and R¹² is —C(O)R¹³. In another embodiment is a compound of Formula(II), or a pharmaceutically acceptable salt thereof, wherein R¹¹ is—C₁₋₈alkyl-C₆₋₁₀aryl optionally substituted with 1, 2, 3, or 4 R¹². Inanother embodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is unsubstituted—C₁₋₈alkyl-C₆₋₁₀aryl. In another embodiment is a compound of Formula(II), or a pharmaceutically acceptable salt thereof, wherein R¹¹ is—C₁₋₈alkyl-C₆₋₁₀aryl substituted with 1, 2, 3, or 4 R¹². In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is —C₁₋₈alkyl-C₆₋₁₀aryl substitutedwith 1, 2, or 3 R¹². In another embodiment is a compound of Formula(II), or a pharmaceutically acceptable salt thereof, wherein R¹¹ is—C₁₋₈alkyl-C₆₋₁₀aryl substituted with 1 or 2 R¹². In another embodimentis a compound of Formula (II), or a pharmaceutically acceptable saltthereof, wherein R¹¹ is —C₁₋₈alkyl-C₆₋₁₀aryl substituted with 1 or 2 R¹²and each R¹² is independently selected from halogen, C₁₋₈alkyl,C₁₋₈haloalkyl, and C₁₋₈alkoxy. In another embodiment is a compound ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein R¹¹is —C₁₋₈alkyl-C₆₋₁₀aryl substituted with 1 or 2 R¹² and each R¹² isindependently selected from C₁₋₈alkyl, C₁₋₈alkoxy, and —C(O)R¹³. Inanother embodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is —C₁₋₈alkyl-C₆₋₁₀aryl substitutedwith 1 or 2 R¹² and each R¹² is independently selected from C₁₋₈alkyl,C₁₋₈haloalkyl, and C₁₋₈alkoxy. In another embodiment is a compound ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein R¹¹is —C₁₋₈alkyl-C₆₋₁₀aryl substituted with 1 or 2 R¹² and each R¹² isindependently selected from C₁₋₈alkyl and C₁₋₈alkoxy. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is —C₁₋₈alkyl-C₆₋₁₀aryl substitutedwith 1 R¹². In another embodiment is a compound of Formula (II), or apharmaceutically acceptable salt thereof, wherein R¹¹ is—C₁₋₈alkyl-C₆₋₁₀aryl substituted with 1 R¹² and R¹² is selected fromhalogen, C₁₋₈alkyl, C₁₋₈haloalkyl, and C₁₋₈alkoxy. In another embodimentis a compound of Formula (II), or a pharmaceutically acceptable saltthereof, wherein R¹¹ is —C₁₋₈alkyl-C₆₋₁₀aryl substituted with 1 R¹² andR¹² is selected from C₁₋₈alkyl, C₁₋₈alkoxy, and —C(O)R¹³. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is —C₁₋₈alkyl-C₆₋₁₀aryl substitutedwith 1 R¹² and R¹² is selected from C₁₋₈alkyl and C₁₋₈alkoxy. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is —C₁₋₈alkyl-C₆₋₁₀aryl substitutedwith 1 R¹² and R¹² is halogen. In another embodiment is a compound ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein R¹¹is —C₁₋₈alkyl-C₆₋₁₀aryl substituted with 1 R¹² and R¹² is —F. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is —C₁₋₈alkyl-C₆₋₁₀aryl substitutedwith 1 R¹² and R¹² is —Cl. In another embodiment is a compound ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein R¹¹is —C₁₋₈alkyl-C₆₋₁₀aryl substituted with 1 R¹² and R¹² is C₁₋₈alkyl. Inanother embodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is —C₁₋₈alkyl-C₆₋₁₀aryl substitutedwith 1 R¹² and R¹² is —CH₃. In another embodiment is a compound ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein R¹¹is —C₁₋₈alkyl-C₆₋₁₀aryl substituted with 1 R¹² and R¹² is C₁₋₈haloalkyl.In another embodiment is a compound of Formula (II), or apharmaceutically acceptable salt thereof, wherein R¹¹ is—C₁₋₈alkyl-C₆₋₁₀aryl substituted with 1 R¹² and R¹² is —CF₃. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is —C₁₋₈alkyl-C₆₋₁₀aryl substitutedwith 1 R¹² and R¹² is C₁₋₈alkoxy. In another embodiment is a compound ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein R¹¹is —C₁₋₈alkyl-C₆₋₁₀aryl substituted with 1 R¹² and R¹² is —OCH₃. Inanother embodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is —C₁₋₈alkyl-C₆₋₁₀aryl substitutedwith 1 R¹² and R¹² is —C(O)R¹³. In another embodiment is a compound ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein R¹¹is —CH₂-phenyl optionally substituted with 1, 2, 3, or 4 R¹². In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is unsubstituted —CH₂-phenyl. Inanother embodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is —CH₂-phenyl substituted with 1,2, 3, or 4 R¹². In another embodiment is a compound of Formula (II), ora pharmaceutically acceptable salt thereof, wherein R¹¹ is —CH₂-phenylsubstituted with 1, 2, or 3 R¹². In another embodiment is a compound ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein R¹¹is —CH₂-phenyl substituted with 1 or 2 R¹². In another embodiment is acompound of Formula (II), or a pharmaceutically acceptable salt thereof,wherein R¹¹ is —CH₂-phenyl substituted with 1 or 2 R¹² and each R¹² isindependently selected from halogen, C₁₋₈alkyl, C₁₋₈haloalkyl, andC₁₋₈alkoxy. In another embodiment is a compound of Formula (II), or apharmaceutically acceptable salt thereof, wherein R¹¹ is —CH₂-phenylsubstituted with 1 or 2 R¹² and each R¹² is independently selected fromC₁₋₈alkyl, C₁₋₈alkoxy, and —C(O)R¹³. In another embodiment is a compoundof Formula (II), or a pharmaceutically acceptable salt thereof, whereinR¹¹ is —CH₂-phenyl substituted with 1 or 2 R¹² and each R¹² isindependently selected from C₁₋₈alkyl, C₁₋₈haloalkyl, and C₁₋₈alkoxy. Inanother embodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is —CH₂-phenyl substituted with 1or 2 R¹² and each R¹² is independently selected from C₁₋₈alkyl andC₁₋₈alkoxy. In another embodiment is a compound of Formula (II), or apharmaceutically acceptable salt thereof, wherein R¹¹ is —CH₂-phenylsubstituted with 1 R¹². In another embodiment is a compound of Formula(II), or a pharmaceutically acceptable salt thereof, wherein R¹¹ is—CH₂-phenyl substituted with 1 R¹² and R¹² is selected from halogen,C₁₋₈alkyl, C₁₋₈haloalkyl, and C₁₋₈alkoxy. In another embodiment is acompound of Formula (II), or a pharmaceutically acceptable salt thereof,wherein R¹¹ is —CH₂-phenyl substituted with 1 R¹² and R¹² is selectedfrom C₁₋₈alkyl, C₁₋₈alkoxy, and —C(O)R¹³. In another embodiment is acompound of Formula (II), or a pharmaceutically acceptable salt thereof,wherein R¹¹ is —CH₂-phenyl substituted with 1 R¹² and R¹² is selectedfrom C₁₋₈alkyl and C₁₋₈alkoxy. In another embodiment is a compound ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein R¹¹is —CH₂-phenyl substituted with 1 R¹² and R¹² is halogen. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is —CH₂-phenyl with 1 R¹² and R¹²is —F. In another embodiment is a compound of Formula (II), or apharmaceutically acceptable salt thereof, wherein R¹¹ is —CH₂-phenylsubstituted with 1 R¹² and R¹² is —Cl. In another embodiment is acompound of Formula (II), or a pharmaceutically acceptable salt thereof,wherein R¹¹ is —CH₂-phenyl substituted with 1 R¹² and R¹² is C₁₋₈alkyl.In another embodiment is a compound of Formula (II), or apharmaceutically acceptable salt thereof, wherein R¹¹ is —CH₂-phenylsubstituted with 1 R¹² and R¹² is —CH₃. In another embodiment is acompound of Formula (II), or a pharmaceutically acceptable salt thereof,wherein R¹¹ is —CH₂-phenyl substituted with 1 R¹² and R¹² isC₁₋₈haloalkyl. In another embodiment is a compound of Formula (II), or apharmaceutically acceptable salt thereof, wherein R¹¹ is —CH₂-phenylsubstituted with 1 R¹² and R¹² is —CF₃. In another embodiment is acompound of Formula (II), or a pharmaceutically acceptable salt thereof,wherein R¹¹ is —CH₂-phenyl substituted with 1 R¹² and R¹² is C₁₋₈alkoxy.In another embodiment is a compound of Formula (II), or apharmaceutically acceptable salt thereof, wherein R¹¹ is —CH₂-phenylsubstituted with 1 R¹² and R¹² is —OCH₃. In another embodiment is acompound of Formula (II), or a pharmaceutically acceptable salt thereof,wherein R¹¹ is —CH₂-phenyl substituted with 1 R¹² and R¹² is —C(O)R¹³.In another embodiment is a compound of Formula (II), or apharmaceutically acceptable salt thereof, wherein R¹¹ is C₂₋₉heteroaryloptionally substituted with 1, 2, 3, or 4 R¹². In another embodiment isa compound of Formula (II), or a pharmaceutically acceptable saltthereof, wherein R¹¹ is unsubstituted C₂₋₉heteroaryl. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is C₂₋₉heteroaryl substituted with1, 2, 3, or 4 R¹². In another embodiment is a compound of Formula (II),or a pharmaceutically acceptable salt thereof, wherein R¹¹ isC₂₋₉heteroaryl substituted with 1, 2, or 3 R¹². In another embodiment isa compound of Formula (II), or a pharmaceutically acceptable saltthereof, wherein R¹¹ is C₂₋₉heteroaryl substituted with 1 or 2 R¹². Inanother embodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is C₂₋₉heteroaryl substituted with1 or 2 R¹² and each R¹² is independently selected from halogen,C₁₋₈alkyl, C₁₋₈haloalkyl, and C₁₋₈alkoxy. In another embodiment is acompound of Formula (II), or a pharmaceutically acceptable salt thereof,wherein R¹¹ is C₂₋₉heteroaryl substituted with 1 or 2 R¹² and each R¹²is independently selected from C₁₋₈alkyl, C₁₋₈alkoxy, and —C(O)R¹³. Inanother embodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is C₂₋₉heteroaryl substituted with1 or 2 R¹² and each R¹² is independently selected from C₁₋₈alkyl,C₁₋₈haloalkyl, and C₁₋₈alkoxy. In another embodiment is a compound ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein R¹¹is C₂₋₉heteroaryl substituted with 1 or 2 R¹² and each R¹² isindependently selected from C₁₋₈alkyl and C₁₋₈alkoxy. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is C₂₋₉heteroaryl substituted with1 R¹². In another embodiment is a compound of Formula (II), or apharmaceutically acceptable salt thereof, wherein R¹¹ is C₂₋₉heteroarylsubstituted with 1 R¹² and R¹² is selected from halogen, C₁₋₈alkyl,C₁₋₈haloalkyl, and C₁₋₈alkoxy. In another embodiment is a compound ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein R¹¹is C₂₋₉heteroaryl substituted with 1 R¹² and R¹² is selected fromC₁₋₈alkyl, C₁₋₈alkoxy, and —C(O)R¹³. In another embodiment is a compoundof Formula (II), or a pharmaceutically acceptable salt thereof, whereinR¹¹ is C₂₋₉heteroaryl substituted with 1 R¹² and R¹² is selected fromC₁₋₈alkyl and C₁₋₈alkoxy. In another embodiment is a compound of Formula(II), or a pharmaceutically acceptable salt thereof, wherein R¹¹ isC₂₋₉heteroaryl substituted with 1 R¹² and R¹² is halogen. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is C₂₋₉heteroaryl substituted with1 R¹² and R¹² is —F. In another embodiment is a compound of Formula(II), or a pharmaceutically acceptable salt thereof, wherein R¹¹ isC₂₋₉heteroaryl substituted with 1 R¹² and R¹² is —Cl. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is C₂₋₉heteroaryl substituted with1 R¹² and R¹² is C₁₋₈alkyl. In another embodiment is a compound ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein R¹¹is C₂₋₉heteroaryl substituted with 1 R¹² and R¹² is —CH₃. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is C₂₋₉heteroaryl substituted with1 R¹² and R¹² is C₁₋₈haloalkyl. In another embodiment is a compound ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein R¹¹is C₂₋₉heteroaryl substituted with 1 R¹² and R¹² is —CF₃. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is C₂₋₉heteroaryl substituted with1 R¹² and R¹² is C₁₋₈alkoxy. In another embodiment is a compound ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein R¹¹is C₂₋₉heteroaryl substituted with 1 R¹² and R¹² is —OCH₃. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is C₂₋₉heteroaryl substituted with1 R¹² and R¹² is —C(O)R¹³. In another embodiment is a compound ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein R¹¹is —C₁₋₈alkyl-C₂₋₉heteroaryl optionally substituted with 1, 2, 3, or 4R¹². In another embodiment is a compound of Formula (II), or apharmaceutically acceptable salt thereof, wherein R¹¹ is unsubstituted—C₁₋₈alkyl-C₂₋₉heteroaryl. In another embodiment is a compound ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein R¹¹is —C₁₋₈alkyl-C₂₋₉heteroaryl substituted with 1, 2, 3, or 4 R¹². Inanother embodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is —C₁₋₈alkyl-C₂₋₉heteroarylsubstituted with 1, 2, or 3 R¹². In another embodiment is a compound ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein R¹¹is —C₁₋₈alkyl-C₂₋₉heteroaryl substituted with 1 or 2 R¹². In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is —C₁₋₈alkyl-C₂₋₉heteroarylsubstituted with 1 or 2 R¹² and each R¹² is independently selected fromhalogen, C₁₋₈alkyl, C₁₋₈haloalkyl, and C₁₋₈alkoxy. In another embodimentis a compound of Formula (II), or a pharmaceutically acceptable saltthereof, wherein R¹¹ is —C₁₋₈alkyl-C₂₋₉heteroaryl substituted with 1 or2 R¹² and each R¹² is independently selected from C₁₋₈alkyl, C₁₋₈alkoxy,and —C(O)R¹³. In another embodiment is a compound of Formula (II), or apharmaceutically acceptable salt thereof, wherein R¹¹ is—C₁₋₈alkyl-C₂₋₉heteroaryl substituted with 1 or 2 R¹² and each R¹² isindependently selected from C₁₋₈alkyl, C₁₋₈haloalkyl, and C₁₋₈alkoxy. Inanother embodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is —C₁₋₈alkyl-C₂₋₉heteroarylsubstituted with 1 or 2 R¹² and each R¹² is independently selected fromC₁₋₈alkyl and C₁₋₈alkoxy. In another embodiment is a compound of Formula(II), or a pharmaceutically acceptable salt thereof, wherein R¹¹ is—C₁₋₈alkyl-C₂₋₉heteroaryl substituted with 1 R¹². In another embodimentis a compound of Formula (II), or a pharmaceutically acceptable saltthereof, wherein R¹¹ is —C₁₋₈alkyl-C₂₋₉heteroaryl substituted with 1 R¹²and R¹² is selected from halogen, C₁₋₈alkyl, C₁₋₈haloalkyl, andC₁₋₈alkoxy. In another embodiment is a compound of Formula (II), or apharmaceutically acceptable salt thereof, wherein R¹¹ is—C₁₋₈alkyl-C₂₋₉heteroaryl substituted with 1 R¹² and R¹² is selectedfrom C₁₋₈alkyl, C₁₋₈alkoxy, and —C(O)R¹³. In another embodiment is acompound of Formula (II), or a pharmaceutically acceptable salt thereof,wherein R¹¹ is —C₁₋₈alkyl-C₂₋₉heteroaryl substituted with 1 R¹² and R¹²is selected from C₁₋₈alkyl and C₁₋₈alkoxy. In another embodiment is acompound of Formula (II), or a pharmaceutically acceptable salt thereof,wherein R¹¹ is —C₁₋₈alkyl-C₂₋₉heteroaryl substituted with 1 R¹² and R¹²is halogen. In another embodiment is a compound of Formula (II), or apharmaceutically acceptable salt thereof, wherein R¹¹ is—C₁₋₈alkyl-C₂₋₉heteroaryl substituted with 1 R¹² and R¹² is —F. Inanother embodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is —C₁₋₈alkyl-C₂₋₉heteroarylsubstituted with 1 R¹² and R¹² is —Cl. In another embodiment is acompound of Formula (II), or a pharmaceutically acceptable salt thereof,wherein R¹¹ is —C₁₋₈alkyl-C₂₋₉heteroaryl substituted with 1 R¹² and R¹²is C₁₋₈alkyl. In another embodiment is a compound of Formula (II), or apharmaceutically acceptable salt thereof, wherein R¹¹ is—C₁₋₈alkyl-C₂₋₉heteroaryl substituted with 1 R¹² and R¹² is —CH₃. Inanother embodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is —C₁₋₈alkyl-C₂₋₉heteroarylsubstituted with 1 R¹² and R¹² is C₁₋₈haloalkyl. In another embodimentis a compound of Formula (II), or a pharmaceutically acceptable saltthereof, wherein R¹¹ is —C₁₋₈alkyl-C₂₋₉heteroaryl substituted with 1 R¹²and R¹² is —CF₃. In another embodiment is a compound of Formula (II), ora pharmaceutically acceptable salt thereof, wherein R¹¹ is—C₁₋₈alkyl-C₂₋₉heteroaryl substituted with 1 R¹² and R¹² is C₁₋₈alkoxy.In another embodiment is a compound of Formula (II), or apharmaceutically acceptable salt thereof, wherein R¹¹ is—C₁₋₈alkyl-C₂₋₉heteroaryl substituted with 1 R¹² and R¹² is —OCH₃. Inanother embodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is —C₁₋₈alkyl-C₂₋₉heteroarylsubstituted with 1 R¹² and R¹² is —C(O)R¹³.

In another embodiment is a compound of Formula (II), or apharmaceutically acceptable salt thereof, wherein R³ is H, —C(O)R⁹, or—C(O)OR⁹. In another embodiment is a compound of Formula (II), or apharmaceutically acceptable salt thereof, wherein R³ is —C(O)R⁹. Inanother embodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R³ is —C(O)R⁹ and R⁹ is C₁₋₁₀alkyl. Inanother embodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R³ is —C(O)R⁹ and R⁹ is C₁₋₆alkyl. Inanother embodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R³ is —C(O)R⁹ and R⁹ is C₁₋₄alkyl. Inanother embodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R³ is —C(O)R⁹ and R⁹ is —CH₃. Inanother embodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R³ is —C(O)R⁹ and R⁹ is —CH₂CH₃. Inanother embodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R³ is —C(O)OR⁹. In another embodimentis a compound of Formula (II), or a pharmaceutically acceptable saltthereof, wherein R³ is —C(O)OR⁹ and R⁹ is C₁₋₁₀alkyl. In anotherembodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R³ is —C(O)OR⁹ and R⁹ is C₁₋₆alkyl. Inanother embodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R³ is —C(O)OR⁹ and R⁹ is C₁₋₄alkyl. Inanother embodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R³ is —C(O)OR⁹ and R⁹ is —CH₃. Inanother embodiment is a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R³ is —C(O)OR⁹ and R⁹ is —CH₂CH₃.

Further embodiments provided herein include combinations of one or moreof the particular embodiments set forth above.

In some embodiments is a compound selected from:

or a pharmaceutically acceptable salt thereof.

In some embodiments is a compound selected from:

or a pharmaceutically acceptable salt thereof.

In some embodiments is a compound selected from:

or a pharmaceutically acceptable salt thereof.

In some embodiments is a compound selected from:

or a pharmaceutically acceptable salt thereof.Preparation of Compounds

The compounds used in the reactions described herein are made accordingto organic synthesis techniques, starting from commercially availablechemicals and/or from compounds described in the chemical literature.“Commercially available chemicals” are obtained from standard commercialsources including Acros Organics (Geel, Belgium), Aldrich Chemical(Milwaukee, Wis., including Sigma Chemical and Fluka), Apin ChemicalsLtd. (Milton Park, UK), Ark Pharm, Inc. (Libertyville, Ill.), AvocadoResearch (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet(Cornwall, U.K.), Chemservice Inc. (West Chester, Pa.), Combi-blocks(San Diego, Calif.), Crescent Chemical Co. (Hauppauge, N.Y.), eMolecules(San Diego, Calif.), Fisher Scientific Co. (Pittsburgh, Pa.), FisonsChemicals (Leicestershire, UK), Frontier Scientific (Logan, Utah), ICNBiomedicals, Inc. (Costa Mesa, Calif.), Key Organics (Cornwall, U.K.),Lancaster Synthesis (Windham, N.H.), Matrix Scientific, (Columbia,S.C.), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co.(Orem, Utah), Pfaltz & Bauer, Inc. (Waterbury, Conn.), Polyorganix(Houston, Tex.), Pierce Chemical Co. (Rockford, Ill.), Riedel de Haen AG(Hanover, Germany), Ryan Scientific, Inc. (Mount Pleasant, S.C.),Spectrum Chemicals (Gardena, Calif.), Sundia Meditech, (Shanghai,China), TCI America (Portland, Oreg.), Trans World Chemicals, Inc.(Rockville, Md.), and WuXi (Shanghai, China).

Suitable reference books and treatises that detail the synthesis ofreactants useful in the preparation of compounds described herein, orprovide references to articles that describe the preparation, includefor example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., NewYork; S. R. Sandler et al., “Organic Functional Group Preparations,” 2ndEd., Academic Press, New York, 1983; H. O. House, “Modern SyntheticReactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L.Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, NewYork, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanismsand Structure”, 4th Ed., Wiley-Interscience, New York, 1992. Additionalsuitable reference books and treatises that detail the synthesis ofreactants useful in the preparation of compounds described herein, orprovide references to articles that describe the preparation, includefor example, Fuhrhop, J. and Penzlin G. “Organic Synthesis: Concepts,Methods, Starting Materials”, Second, Revised and Enlarged Edition(1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R. V. “OrganicChemistry, An Intermediate Text” (1996) Oxford University Press, ISBN0-19-509618-5; Larock, R. C. “Comprehensive Organic Transformations: AGuide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH,ISBN: 0-471-19031-4; March, J. “Advanced Organic Chemistry: Reactions,Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN:0-471-60180-2; Otera, J. (editor) “Modern Carbonyl Chemistry” (2000)Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. “Patai's 1992 Guide to theChemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022-9;Solomons, T. W. G. “Organic Chemistry” 7th Edition (2000) John Wiley &Sons, ISBN: 0-471-19095-0; Stowell, J. C., “Intermediate OrganicChemistry” 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2;“Industrial Organic Chemicals: Starting Materials and Intermediates: AnUllmann's Encyclopedia” (1999) John Wiley & Sons, ISBN: 3-527-29645-X,in 8 volumes; “Organic Reactions” (1942-2000) John Wiley & Sons, in over55 volumes; and “Chemistry of Functional Groups” John Wiley & Sons, in73 volumes.

Specific and analogous reactants are also identified through the indicesof known chemicals prepared by the Chemical Abstract Service of theAmerican Chemical Society, which are available in most public anduniversity libraries, as well as through on-line databases (the AmericanChemical Society, Washington, D.C.). Chemicals that are known but notcommercially available in catalogs are optionally prepared by customchemical synthesis houses, where many of the standard chemical supplyhouses (e.g., those listed above) provide custom synthesis services. Areference for the preparation and selection of pharmaceutical salts ofthe compounds described herein is P. H. Stahl & C. G. Wermuth “Handbookof Pharmaceutical Salts”, Verlag Helvetica Chimica Acta, Zurich, 2002.

Further Forms of Compounds Disclosed Herein

Isomers

Furthermore, in some embodiments, the compounds described herein existas geometric isomers. In some embodiments, the compounds describedherein possess one or more double bonds. The compounds presented hereininclude all cis, trans, syn, anti, entgegen (F), and zusammen (Z)isomers as well as the corresponding mixtures thereof. In somesituations, compounds exist as tautomers. The compounds described hereininclude all possible tautomers within the formulas described herein. Insome situations, the compounds described herein possess one or morechiral centers and each center exists in the R configuration or Sconfiguration. The compounds described herein include alldiastereomeric, enantiomeric, and epimeric forms as well as thecorresponding mixtures thereof. In additional embodiments of thecompounds and methods provided herein, mixtures of enantiomers and/ordiastereoisomers, resulting from a single preparative step, combination,or interconversion, are useful for the applications described herein. Insome embodiments, the compounds described herein are prepared asoptically pure enantiomers by chiral chromatographic resolution of theracemic mixture. In some embodiments, the compounds described herein areprepared as their individual stereoisomers by reacting a racemic mixtureof the compound with an optically active resolving agent to form a pairof diastereoisomeric compounds, separating the diastereomers andrecovering the optically pure enantiomers. In some embodiments,dissociable complexes are preferred (e.g., crystalline diastereomericsalts). In some embodiments, the diastereomers have distinct physicalproperties (e.g., melting points, boiling points, solubilities,reactivity, etc.) and are separated by taking advantage of thesedissimilarities. In some embodiments, the diastereomers are separated bychiral chromatography, or preferably, by separation/resolutiontechniques based upon differences in solubility. In some embodiments,the optically pure enantiomer is then recovered, along with theresolving agent, by any practical means that does not result inracemization.

Labeled Compounds

In some embodiments, the compounds described herein exist in theirisotopically-labeled forms. In some embodiments, the methods disclosedherein include methods of treating diseases by administering suchisotopically-labeled compounds. In some embodiments, the methodsdisclosed herein include methods of treating diseases by administeringsuch isotopically-labeled compounds as pharmaceutical compositions.Thus, in some embodiments, the compounds disclosed herein includeisotopically-labeled compounds, which are identical to those recitedherein, but for the fact that one or more atoms are replaced by an atomhaving an atomic mass or mass number different from the atomic mass ormass number usually found in nature. Examples of isotopes that areincorporated into compounds described herein include isotopes ofhydrogen, carbon, nitrogen, oxygen, Phosphorous, sulfur, fluorine, andchloride, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F,and ³⁶Cl, respectively. Compounds described herein, and pharmaceuticallyacceptable salts, esters, solvate, hydrates or derivatives thereof whichcontain the aforementioned isotopes and/or other isotopes of other atomsare within the scope of this invention. Certain isotopically-labeledcompounds, for example those into which radioactive isotopes such as ³Hand ¹⁴C are incorporated, are useful in drug and/or substrate tissuedistribution assays. Tritiated, i.e., ³H and carbon-14, i.e., ¹⁴C,isotopes are particularly preferred for their ease of preparation anddetectability. Further, substitution with heavy isotopes such asdeuterium, i.e., ²H, produces certain therapeutic advantages resultingfrom greater metabolic stability, for example increased in vivohalf-life or reduced dosage requirements. In some embodiments, theisotopically labeled compounds, pharmaceutically acceptable salt, ester,solvate, hydrate, or derivative thereof is prepared by any suitablemethod.

In some embodiments, the compounds described herein are labeled by othermeans, including, but not limited to, the use of chromophores orfluorescent moieties, bioluminescent labels, or chemiluminescent labels.

Pharmaceutically Acceptable Salts

In some embodiments, the compounds described herein exist as theirpharmaceutically acceptable salts. In some embodiments, the methodsdisclosed herein include methods of treating diseases by administeringsuch pharmaceutically acceptable salts. In some embodiments, the methodsdisclosed herein include methods of treating diseases by administeringsuch pharmaceutically acceptable salts as pharmaceutical compositions.

In some embodiments, the compounds described herein possess acidic orbasic groups and therefore react with any of a number of inorganic ororganic bases, and inorganic and organic acids, to form apharmaceutically acceptable salt. In some embodiments, these salts areprepared in situ during the final isolation and purification of thecompounds described herein, or by separately reacting a purifiedcompound in its free form with a suitable acid or base, and isolatingthe salt thus formed.

Solvates

In some embodiments, the compounds described herein exist as solvates.In some embodiments are methods of treating diseases by administeringsuch solvates. Further described herein are methods of treating diseasesby administering such solvates as pharmaceutical compositions.

Solvates contain either stoichiometric or non-stoichiometric amounts ofa solvent, and, in some embodiments, are formed during the process ofcrystallization with pharmaceutically acceptable solvents such as water,ethanol, and the like. Hydrates are formed when the solvent is water, oralcoholates are formed when the solvent is alcohol. Solvates of thecompounds described herein are conveniently prepared or formed duringthe processes described herein. By way of example only, hydrates of thecompounds described herein are conveniently prepared byrecrystallization from an aqueous/organic solvent mixture, using organicsolvents including, but not limited to, dioxane, tetrahydrofuran orMeOH. In addition, the compounds provided herein exist in unsolvated aswell as solvated forms. In general, the solvated forms are consideredequivalent to the unsolvated forms for the purposes of the compounds andmethods provided herein.

Pharmaceutical Compositions

In certain embodiments, the compound of Formula (I), (I′), (Ia), (Ib),(Ic), or (II) as described herein is administered as a pure chemical. Insome embodiments, the compound of Formula (I), (I′), (Ia), (Ib), (Ic),or (II) described herein is combined with a pharmaceutically suitable oracceptable carrier (also referred to herein as a pharmaceuticallysuitable (or acceptable) excipient, physiologically suitable (oracceptable) excipient, or physiologically suitable (or acceptable)carrier) selected on the basis of a chosen route of administration andstandard pharmaceutical practice as described, for example, inRemington: The Science and Practice of Pharmacy (Gennaro, 21^(st) Ed.Mack Pub. Co., Easton, Pa. (2005)).

Accordingly, provided herein is a pharmaceutical composition comprisingat least one compound of Formula (I), (I′), (Ia), (Ib), (Ic), or (II)described herein, or a stereoisomer, pharmaceutically acceptable salt,hydrate, solvate, or N-oxide thereof, together with one or morepharmaceutically acceptable carriers. The carrier(s) (or excipient(s))is acceptable or suitable if the carrier is compatible with the otheringredients of the composition and not deleterious to the recipient(i.e., the subject) of the composition.

One embodiment provides a pharmaceutical composition comprising apharmaceutically acceptable excipient and a compound of Formula (I), ora pharmaceutically acceptable salt thereof. Another embodiment providesa pharmaceutical composition comprising a pharmaceutically acceptableexcipient and a compound of Formula (I′), or a pharmaceuticallyacceptable salt thereof. Another embodiment provides a pharmaceuticalcomposition comprising a pharmaceutically acceptable excipient and acompound of Formula (Ia), or a pharmaceutically acceptable salt thereof.Another embodiment provides a pharmaceutical composition comprising apharmaceutically acceptable excipient and a compound of Formula (Ib), ora pharmaceutically acceptable salt thereof. Another embodiment providesa pharmaceutical composition comprising a pharmaceutically acceptableexcipient and a compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof. Another embodiment provides a pharmaceuticalcomposition comprising a pharmaceutically acceptable excipient and acompound of Formula (II), or a pharmaceutically acceptable salt thereof.

Another embodiment provides a pharmaceutical composition consistingessentially of a pharmaceutically acceptable excipient and a compound ofFormula (I), or a pharmaceutically acceptable salt thereof. Anotherembodiment provides a pharmaceutical composition consisting essentiallyof a pharmaceutically acceptable excipient and a compound of Formula(I′), or a pharmaceutically acceptable salt thereof. Another embodimentprovides a pharmaceutical composition consisting essentially of apharmaceutically acceptable excipient and a compound of Formula (Ia), ora pharmaceutically acceptable salt thereof. Another embodiment providesa pharmaceutical composition consisting essentially of apharmaceutically acceptable excipient and a compound of Formula (Ib), ora pharmaceutically acceptable salt thereof. Another embodiment providesa pharmaceutical composition consisting essentially of apharmaceutically acceptable excipient and a compound of Formula (Ic), ora pharmaceutically acceptable salt thereof. Another embodiment providesa pharmaceutical composition consisting essentially of apharmaceutically acceptable excipient and a compound of Formula (II), ora pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I), (I′), (Ia), (Ib),(Ic), or (II) as described herein is substantially pure, in that itcontains less than about 5%, or less than about 1%, or less than about0.1%, of other organic small molecules, such as contaminatingintermediates or by-products that are created, for example, in one ormore of the steps of a synthesis method.

In certain embodiments, the compound of Formula (I), (I′), (Ia), (Ib),(Ic), or (II) described herein is formulated for oral, rectal, topical,buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, orintravenous), vaginal, ophthalmic, or aerosol administration, althoughthe most suitable form of administration in any given case will dependon the degree and severity of the condition being treated and on thenature of the particular compound being used. For example, disclosedcompositions are formulated as a unit dose, and/or are formulated fororal or subcutaneous administration.

Exemplary pharmaceutical compositions are used in the form of apharmaceutical preparation, for example, in solid, semisolid or liquidform, which includes one or more of a disclosed compound, as an activeingredient, in a mixture with an organic or inorganic carrier orexcipient suitable for external, enteral or parenteral applications. Insome embodiments, the active ingredient is compounded, for example, withthe usual non-toxic, pharmaceutically acceptable carriers for tablets,pellets, capsules, suppositories, solutions, emulsions, suspensions, andany other form suitable for use. The active object compound is includedin the pharmaceutical composition in an amount sufficient to produce thedesired effect upon the process or condition of the disease.

In some embodiments for preparing solid compositions such as tablets,the principal active ingredient is mixed with a pharmaceutical carrier,e.g., conventional tableting ingredients such as corn starch, lactose,sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalciumphosphate, or gums, and other pharmaceutical diluents, e.g., water, toform a solid preformulation composition containing a homogeneous mixtureof a disclosed compound or a non-toxic pharmaceutically acceptable saltthereof. When referring to these preformulation compositions ashomogeneous, it is meant that the active ingredient is dispersed evenlythroughout the composition so that the composition is readily subdividedinto equally effective unit dosage forms such as tablets, pills andcapsules.

In solid dosage forms for oral administration (capsules, tablets, pills,dragees, powders, granules and the like), the subject composition ismixed with one or more pharmaceutically acceptable carriers, such assodium citrate or dicalcium phosphate, and/or any of the following: (1)fillers or extenders, such as starches, cellulose, microcrystallinecellulose, silicified microcrystalline cellulose, lactose, sucrose,glucose, mannitol, and/or silicic acid; (2) binders, such as, forexample, carboxymethylcellulose, hypromellose, alginates, gelatin,polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such asglycerol; (4) disintegrating agents, such as crospovidone,croscarmellose sodium, sodium starch glycolate, agar-agar, calciumcarbonate, potato or tapioca starch, alginic acid, certain silicates,and sodium carbonate; (5) solution retarding agents, such as paraffin;(6) absorption accelerators, such as quaternary ammonium compounds; (7)wetting agents, such as, for example, docusate sodium, cetyl alcohol andglycerol monostearate; (8) absorbents, such as kaolin and bentoniteclay; (9) lubricants, such a talc, calcium stearate, magnesium stearate,solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof;and (10) coloring agents. In the case of capsules, tablets and pills, insome embodiments, the compositions comprise buffering agents. In someembodiments, solid compositions of a similar type are also employed asfillers in soft and hard-filled gelatin capsules using such excipientsas lactose or milk sugars, as well as high molecular weight polyethyleneglycols and the like.

In some embodiments, a tablet is made by compression or molding,optionally with one or more accessory ingredients. In some embodiments,compressed tablets are prepared using binder (for example, gelatin orhydroxypropylmethyl cellulose), lubricant, inert diluent, preservative,disintegrant (for example, sodium starch glycolate or cross-linkedsodium carboxymethyl cellulose), surface-active or dispersing agent. Insome embodiments, molded tablets are made by molding in a suitablemachine a mixture of the subject composition moistened with an inertliquid diluent. In some embodiments, tablets, and other solid dosageforms, such as dragees, capsules, pills, and granules, are scored orprepared with coatings and shells, such as enteric coatings and othercoatings.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable aqueous or organic solvents,or mixtures thereof, and powders. Liquid dosage forms for oraladministration include pharmaceutically acceptable emulsions,microemulsions, solutions, suspensions, syrups, and elixirs. In additionto the subject composition, in some embodiments, the liquid dosage formscontain inert diluents, such as, for example, water or other solvents,solubilizing agents and emulsifiers, such as ethyl alcohol, isopropylalcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylene glycol, oils (optionally,cottonseed, groundnut, corn, germ, olive, castor and sesame oils),glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acidesters of sorbitan, cyclodextrins, and mixtures thereof.

In some embodiments, suspensions, in addition to the subjectcomposition, contain suspending agents as, for example, ethoxylatedisostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters,microcrystalline cellulose, aluminum metahydroxide, bentonite,agar-agar, tragacanth, and mixtures thereof.

In some embodiments, formulations for rectal or vaginal administrationare presented as a suppository, which are prepared by mixing a subjectcomposition with one or more suitable non-irritating excipients orcarriers comprising, for example, cocoa butter, polyethylene glycol, asuppository wax or a salicylate, and which is solid at room temperature,but liquid at body temperature and, therefore, will melt in the bodycavity and release the active agent.

Dosage forms for transdermal administration of a subject compositioninclude powders, sprays, ointments, pastes, creams, lotions, gels,solutions, patches and inhalants. In some embodiments, the activecomponent is mixed under sterile conditions with a pharmaceuticallyacceptable carrier, and with any preservatives, buffers, or propellantsas required.

In some embodiments, the ointments, pastes, creams and gels contain, inaddition to a subject composition, excipients, such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc, and zinc oxide, or mixtures thereof.

In some embodiments, powders and sprays contain, in addition to asubject composition, excipients such as lactose, talc, silicic acid,aluminum hydroxide, calcium silicates and polyamide powder, or mixturesof these substances. In some embodiments, sprays additionally containcustomary propellants, such as chlorofluorohydrocarbons and volatileunsubstituted hydrocarbons, such as butane and propane.

In some embodiments, the compounds described herein are formulated aseye drops for ophthalmic administration.

Compositions and compounds disclosed herein alternatively areadministered by aerosol. This is accomplished by preparing an aqueousaerosol, liposomal preparation or solid particles containing thecompound. In some embodiments, a non-aqueous (e.g., fluorocarbonpropellant) suspension is used. In some embodiments, sonic nebulizersare used because they minimize exposing the agent to shear, whichresults in degradation of the compounds contained in the subjectcompositions. Ordinarily, an aqueous aerosol is made by formulating anaqueous solution or suspension of a subject composition together withconventional pharmaceutically acceptable carriers and stabilizers. Thecarriers and stabilizers vary with the requirements of the particularsubject composition, but typically include non ionic surfactants(Tweens, Pluronics, or polyethylene glycol), sorbitan esters, oleicacid, lecithin, amino acids such as glycine, buffers, salts, sugars, orsugar alcohols. Aerosols generally are prepared from isotonic solutions.

Pharmaceutical compositions suitable for parenteral administrationcomprise a subject composition in combination with one or morepharmaceutically-acceptable sterile isotonic aqueous or non-aqueoussolutions, dispersions, suspensions or emulsions, or sterile powderswhich are reconstituted into sterile injectable solutions or dispersionsjust prior to use, which, in some embodiments, contain antioxidants,buffers, bacteriostats, solutes which render the formulation isotonicwith the blood of the intended recipient or suspending or thickeningagents.

Examples of suitable aqueous and non-aqueous carriers which are employedin the pharmaceutical compositions include water, ethanol, polyols (suchas glycerol, propylene glycol, polyethylene glycol, and the like), andsuitable mixtures thereof, vegetable oils such as olive oil, andinjectable organic esters such as ethyl oleate and cyclodextrins. Properfluidity is maintained, for example, by the use of coating materials,such as lecithin, by the maintenance of the required particle size inthe case of dispersions, and by the use of surfactants.

Also contemplated are enteral pharmaceutical formulations including adisclosed compound, an enteric material, and a pharmaceuticallyacceptable carrier or excipient thereof. Enteric materials refer topolymers that are substantially insoluble in the acidic environment ofthe stomach, and that are predominantly soluble in intestinal fluids atspecific pHs. The small intestine is the part of the gastrointestinaltract (gut) between the stomach and the large intestine, and includesthe duodenum, jejunum, and ileum. The pH of the duodenum is about 5.5,the pH of the jejunum is about 6.5 and the pH of the distal ileum isabout 7.5. Accordingly, enteric materials are not soluble, for example,until a pH of about 5.0, of about 5.2, of about 5.4, of about 5.6, ofabout 5.8, of about 6.0, of about 6.2, of about 6.4, of about 6.6, ofabout 6.8, of about 7.0, of about 7.2, of about 7.4, of about 7.6, ofabout 7.8, of about 8.0, of about 8.2, of about 8.4, of about 8.6, ofabout 8.8, of about 9.0, of about 9.2, of about 9.4, of about 9.6, ofabout 9.8, or of about 10.0. Exemplary enteric materials includecellulose acetate phthalate (CAP), hydroxypropyl methylcellulosephthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), cellulose acetatetrimellitate, hydroxypropyl methylcellulose succinate, cellulose acetatesuccinate, cellulose acetate hexahydrophthalate, cellulose propionatephthalate, cellulose acetate maleate, cellulose acetate butyrate,cellulose acetate propionate, copolymer of methylmethacrylic acid andmethyl methacrylate, copolymer of methyl acrylate, methylmethacrylateand methacrylic acid, copolymer of methylvinyl ether and maleicanhydride (Gantrez ES series), ethylmethyacrylate-methylmethacrylate-chlorotrimethylammonium ethyl acrylatecopolymer, natural resins such as zein, shellac and copal collophorium,and several commercially available enteric dispersion systems (e.g.,Eudragit L30D55, Eudragit FS30D, Eudragit L100, Eudragit S100, KollicoatEMM30D, Estacryl 30D, Coateric, and Aquateric). The solubility of eachof the above materials is either known or is readily determinable invitro.

The dose of the composition comprising at least one compound of Formula(I), (I′), (Ia), (Ib), (Ic), or (II) as described herein differs,depending upon the patient's (e.g., human) condition, that is, stage ofthe disease, general health status, age, and other factors.

Pharmaceutical compositions are administered in a manner appropriate tothe disease to be treated (or prevented). An appropriate dose and asuitable duration and frequency of administration will be determined bysuch factors as the condition of the patient, the type and severity ofthe patient's disease, the particular form of the active ingredient, andthe method of administration. In general, an appropriate dose andtreatment regimen provides the composition(s) in an amount sufficient toprovide therapeutic and/or prophylactic benefit (e.g., an improvedclinical outcome, such as more frequent complete or partial remissions,or longer disease-free and/or overall survival, or a lessening ofsymptom severity. Optimal doses are generally determined usingexperimental models and/or clinical trials. In some embodiments, theoptimal dose depends upon the body mass, weight, or blood volume of thepatient.

Oral doses typically range from about 1.0 mg to about 1000 mg, one tofour times, or more, per day.

Methods

In some embodiments is a method of treating cancer in a patient in needthereof, comprising administering to the patient a therapeuticallyeffective amount of a compound of Formula (I), (I′), (Ia), (Ib), (Ic),or (II) described herein, or a pharmaceutically acceptable salt thereof.In some embodiments is a method of treating cancer in a patient in needthereof, comprising administering to the patient a therapeuticallyeffective amount of a compound of Formula (I), (I′), (Ia), (Ib), (Ic),or (II) described herein, or a pharmaceutically acceptable salt thereof,wherein the cancer is breast cancer, ovarian cancer, non-small cell lungcancer, pancreatic cancer, or bladder cancer. In some embodiments is amethod of treating breast cancer in a patient in need thereof,comprising administering to the patient a therapeutically effectiveamount of a compound of Formula (I), (I′), (Ia), (Ib), (Ic), or (II)described herein, or a pharmaceutically acceptable salt thereof. In someembodiments is a method of treating ovarian cancer in a patient in needthereof, comprising administering to the patient a therapeuticallyeffective amount of a compound of Formula (I), (I′), (Ia), (Ib), (Ic),or (II) described herein, or a pharmaceutically acceptable salt thereof.In some embodiments is a method of treating non-small cell lung cancerin a patient in need thereof, comprising administering to the patient atherapeutically effective amount of a compound of Formula (I), (I′),(Ia), (Ib), (Ic), or (II) described herein, or a pharmaceuticallyacceptable salt thereof. In some embodiments is a method of treatingpancreatic cancer in a patient in need thereof, comprising administeringto the patient a therapeutically effective amount of a compound ofFormula (I), (I′), (Ia), (Ib), (Ic), or (II) described herein, or apharmaceutically acceptable salt thereof. In some embodiments is amethod of treating bladder cancer in a patient in need thereof,comprising administering to the patient a therapeutically effectiveamount of a compound of Formula (I), (I′), (Ia), (Ib), (Ic), or (II)described herein, or a pharmaceutically acceptable salt thereof.

In some embodiments is a method of treating an infectious disease in apatient in need thereof, comprising administering to the patient atherapeutically effective amount of a compound of Formula (I), (I′),(Ia), (Ib), (Ic), or (II) described herein, or a pharmaceuticallyacceptable salt thereof.

In certain embodiments, a disclosed compound utilized by one or more ofthe foregoing methods is one of the generic, subgeneric, or specificcompounds described herein, such as a compound of Formula (I), (I′),(Ia), (Ib), (Ic), or (II).

Disclosed compounds are administered to patients (animals and humans) inneed of such treatment in dosages that will provide optimalpharmaceutical efficacy. It will be appreciated that the dose requiredfor use in any particular application will vary from patient to patient,not only with the particular compound or composition selected, but alsowith the route of administration, the nature of the condition beingtreated, the age and condition of the patient, concurrent medication orspecial diets then being followed by the patient, and other factors,with the appropriate dosage ultimately being at the discretion of theattendant physician. For treating clinical conditions and diseases notedabove, a contemplated compound disclosed herein is administered orally,subcutaneously, topically, parenterally, by inhalation spray, orrectally in dosage unit formulations containing conventional non-toxicpharmaceutically acceptable carriers, adjuvants and vehicles. Parenteraladministration include subcutaneous injections, intravenous, orintramuscular injections or infusion techniques.

The following examples are provided merely as illustrative of variousembodiments and shall not be construed to limit the invention in anyway.

EXAMPLES List of Abbreviations

As used above, and throughout the description of the invention, thefollowing abbreviations, unless otherwise indicated, shall be understoodto have the following meanings:

-   ACN acetonitrile-   Bn benzyl-   BOC or Boc tert-butyl carbamate-   DCC dichloroethane (ClCH₂CH₂Cl)-   DCM N,N′-dicyclohexylcarbodiimide-   DIPEA N,N-diisopropylethylamine-   DMAP 4-(N,N-dimethylamino)pyridine-   DMF dimethylformamide-   DMA N,N-dimethylacetamide-   DMSO dimethylsulfoxide-   equiv equivalent(s)-   EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide-   Et ethyl-   EtOH ethanol-   EtOAc ethyl acetate-   HF hydrofluoric acid-   HMDS bis(trimethylsilyl)amine-   HPLC high performance liquid chromatography-   Me methyl-   MeOH methanol-   MMTr 4-methoxytrityl-   MMTrCl 4-methoxytrityl chloride-   MS mass spectroscopy-   NMM N-methylmorpholine-   NMR nuclear magnetic resonance-   TBHP tert-butyl hydroperoxide-   TEA triethylamine-   TFA trifluoroacetic acid-   THE tetrahydrofuran-   TLC thin layer chromatography-   TBDMSCl tert-butyldimethylsilyl chloride-   TMSCl trimethylsilyl chloride-   TMSOTf trimethylsilyl trifluoromethanesulfonate    Chemical Synthesis

Unless otherwise noted, reagents and solvents were used as received fromcommercial suppliers. Anhydrous solvents and oven-dried glassware wereused for synthetic transformations sensitive to moisture and/or oxygen.Yields were not optimized. Reaction times are approximate and were notoptimized. Column chromatography and thin layer chromatography (TLC)were performed on silica gel unless otherwise noted. Spectra are givenin ppm (δ) and coupling constants (J) are reported in Hertz. For protonspectra the solvent peak was used as the reference peak.

Synthesis of Intermediates:

Synthesis of Int-C:

To a solution of PCl₃ (7.7 mL, 87.9 mmol) in diethyl ether (60 mL) wasadded Int-A (16.7 mL, 118.8 mmol) in diethyl ether (60 mL) dropwise overa period of 1 h at 0° C. The reaction mixture was stirred at roomtemperature for 4 h under argon atmosphere. The reaction mixture wasthen filtered and washed with diethyl ether (20 mL). The filtrate wasconcentrated under reduced pressure to give Int-B (13 g) as a colorlessliquid. The compound was used directly in the next step without anyfurther purification.

To a solution of 1-hexanol (13.13 g, 128.0 mmol) in hexane (65 mL) wasadded DIPEA (67.2 mL, 386.0 mmol) followed by Int-B (13.0 g, 64.0 mmol)in hexane (65 mL) dropwise over a period of 1 h at 10° C. The reactionmixture was stirred at room temperature for 4 h and then concentratedunder reduced pressure to afford Int-C (16 g) as a light green liquid.The compound was used directly in the next step without any furtherpurification.

Synthesis of Int-E:

To a solution of Int-D (10.0 g, 80.0 mmol) in diethyl ether (300 mL) wasadded PCl₃ (8.2 mL, 94.2 mmol) over a period of 15 min at −20° C., andthen pyridine (19.1 mL, 241.9 mmol) in diethyl ether (200 mL) was addeddropwise over a period of 2 h at −20° C. The reaction mixture wasallowed to warm to room temperature and maintained at room temperaturefor 2 h. The reaction mixture was stored at 0° C. for 12 h and filtered.The filtrate was concentrated under reduced pressure to afford crudeInt-E (12 g, 80%) as a yellow oil. The compound was used directly in thenext step without any further purification.

Synthesis of Int-I:

To a stirred solution of Int-F (20 g, 142.8 mmol) in ACN (200 mL) wasadded NaI (63.8 g, 428.4 mmol) and chloromethylpivalate (85.7 g, 571.4mmol) at room temperature. The resulting reaction mixture was heated to80° C. for 3 days. The reaction mixture was cooled and concentratedunder reduced pressure. The residue was dissolved in ethyl acetate (200mL) and washed with water (50 mL) and brine (50 mL). The organic layerwas dried over anhydrous Na₂SO₄ and filtered. The solvent was evaporatedunder reduced pressure and the residue was purified by silica gelchromatography to afford Int-G (40 g, 62%) as a light green liquid.

A solution of Int-G (40 g, 90.0 mmol) in piperidine (280 mL) was stirredat room temperature for 12 h. The reaction mixture was distilled. Thecrude compound was dissolved in water (240 mL) and Dowex H⁺ resin wasadded till pH˜2 and stirred for 2 h at room temperature. The reactionmixture was filtered and washed with water (2×50 mL). The filtrate wasconcentrated under reduced pressure to afford pure Int-H (15 g, 51%) asan off-white solid.

To a solution of Int-H (10 g, 30.6 mmol) in DCM (100 mL) was addedoxalyl chloride in DCM (100 mL) dropwise at room temperature under argonatmosphere. The reaction mixture was stirred for 2 h at roomtemperature. The reaction mixture was concentrated under reducedpressure to afford Int-I (10 g) as a yellow oil. The compound was useddirectly in the next step without any further purification.

Synthesis of Int-J:

To a stirred solution of phosphorus oxychloride (3.7 mL, 39.7 mmol) indistilled tetrahydrofuran (50 mL) was added 1-decanol (5.0 g, 31.59mmol) as a solution in pyridine (7.7 mL, 95.6 mmol) at 0° C. underargon. The reaction mixture was stirred at 0° C. for 1 h. The reactionwas quenched by dropwise addition of saturated aqueous sodiumbicarbonate (140 mL) at 0° C. The mixture was poured onto ice water (150mL) and the mixture was acidified to pH 2 by addition of 6 Mhydrochloric acid. The mixture was extracted with ethyl acetate (3×100mL). The combined organic layers were washed with water (100 mL) andbrine (100 mL), dried over anhydrous magnesium sulfate and evaporated togive Int-J (6.50 g, 86%) as a pale yellow semi-solid.

Synthesis of Int-K:

Dry Et₃N (15.54 g, 153.58 mmol, 1 eq.) and octan-1-ol (20 g, 153.58mmol, 1 eq.) in Et₂O (150 mL) was added dropwise with vigorous stirringto POCl₃ (23.55 g, 153.58 mmol, 1 eq.) in Et₂O (150 mL) at −78° C. underN₂. After addition, the reaction mixture was allowed to warm to 25° C.and stirred for 12 h. The mixture was filtered and the filtrate wasconcentrated in reduced pressure to yield 1-dichlorophosphoryloxyoctane(20 g, 53% yield) as a yellow liquid. ¹H NMR (400 MHz, CDCl₃) δ 4.36(td, J=6.4, 9.8 Hz, 2H), 1.90-1.78 (m, 2H), 1.51-1.42 (m, 2H), 1.39-1.28(m, 8H), 1.02-0.81 (m, 3H).

Example 1: Synthesis of(2R,3R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-(((bis(hexyloxy)phosphoryl)oxy)methyl)-4,4-difluorotetrahydrofuran-3-ylnonanoate (Compound 1)

To a suspension of 11 (40 g, 152.0 mmol) in HMDS (73.46 g, 456.2 mmol)were added DMAP (1.8 g, 15.2 mmol) and TMSOTf (1.01 g, 4.56 mmol) at 0°C. The resulting mixture was stirred at room temperature for 12 h.Boc-anhydride (165 g, 760 mmol) was then added dropwise over a period of1 h at 0° C. The resulting reaction mixture was stirred at roomtemperature for 16 h and then methanol (400 mL) and TEA (200 mL) wereadded at 0° C. for 1 h. The resulting reaction mixture was stirred atroom temperature for 20 h. The reaction mixture was concentrated underreduced pressure and the residue was diluted with water (100 mL) andextracted with ethyl acetate (3×200 mL). The combined organic layerswere washed with water (100 mL) and brine (100 mL). The organic layerwas dried over anhydrous Na₂SO₄, filtered and the solvent was evaporatedunder reduced pressure. The crude compound was purified by silica gelchromatography to afford 4a (35.0 g, 63%) and 4b (12 g, 17%) asoff-white solids.

To a stirred solution of 4a (35.0 g, 96.4 mmol) in pyridine (350 mL) at0° C. were added imidazole (9.18 g, 134.9 mmol) and TBDMSCl (26.03 g,173.5 mmol). The reaction mixture was stirred at room temperature for 8h. The pyridine was evaporated under reduced pressure and the residuewas co-distilled with toluene repeatedly 3 times. The crude reactionmass was diluted with water (100 mL) and extracted with ethyl acetate(3×200 mL). The combined organic layers were washed with water (100 mL)and brine (100 mL). The organic layer was dried over anhydrous Na₂SO₄,filtered, and the solvent was evaporated under reduced pressure. Thecrude product was purified by silica gel chromatography to afford 5 (30g, 65%) as an off-white solid.

To a solution of 5 (30 g, 62.8 mmol) in 1,4-dioxane (300 mL) at 0° C.was added TEA (43.7 mL, 314.4 mmol), DCC (38.86 g, 188.0 mmol), and DMAP(767 mg, 6.2 mmol) followed by nonanoic acid (29.81 g, 188 mmol). Thereaction mixture was stirred at room temperature overnight. The solventwas evaporated under reduced pressure and the residue was dissolved inDCM (500 mL) and washed with water (100 mL) and brine (100 mL). Theorganic layer was dried over anhydrous Na₂SO₄ and filtered. The solventwas evaporated under reduced pressure to give the crude compound whichwas purified by silica gel chromatography to afford 6 (30 g, 77%) as alight brown liquid.

To a solution of 6 (30 g, 48.6 mmol) in THE (300 mL), was added TEA.3HF(39.14 g, 243 mmol) dropwise at 0° C. The reaction mixture was slowlywarmed to room temperature and stirred for 12 h at room temperature. Thesolvent was evaporated under reduced pressure and the residue wasdissolved in ethyl acetate (500 mL) and washed with water (100 mL) andbrine (100 mL). The organic layer was dried over anhydrous Na₂SO₄ andfiltered. The solvent was evaporated under reduced pressure to give thecrude compound which was purified by silica gel chromatography to afford7 (20 g, 82%) as a light brown liquid.

To a stirred solution of 7 (5 g, 9.9 mmol) in DCM (100 mL), was addedDIPEA (8.65 mL, 49.6 mmol) and tetrazole (1.74 g, 24.8 mmol). Int-C(8.27 g, 24.8 mmol) in DCM (20 mL) was then added dropwise at 0° C. over15 min. The reaction mixture was stirred at room temperature for 16 hand then TBHP (5.96 ml; 5M in decane, 29.8 mmol) was added to thereaction mixture dropwise at 0° C. The resulting reaction mixture wasstirred for 6 h at room temperature. The reaction mixture wasconcentrated under reduced pressure and the residue was dissolved inethyl acetate (100 mL) and washed with water (50 mL) and brine (50 mL).The organic layer was dried over anhydrous Na₂SO₄ filtered solvent wasevaporated under reduced pressure to give the crude compound which waspurified by silica gel chromatography to afford 8 (2.8 g, 38%) as a redliquid.

To a solution of 8 (2.8 g, 3.72 mmol) in DCM (28 mL) was added TFA (1.42mL, 18.6 mmol) dropwise at 0° C. The reaction mixture was stirred atroom temperature for 16 h. The solvent was evaporated under reducedpressure and the residue was diluted in ethyl acetate (200 mL) andwashed with saturated NaHCO₃ (2×50 mL). The organic layer was dried overNa₂SO₄ and filtered. The solvent was evaporated under reduced pressureto give the crude compound which was purified by silica gelchromatography to afford the title compound (1) (1.3 g, 54%) as acolorless liquid. ¹H NMR (300 MHz, d₆-DMSO): δ 0.83-0.87 (9H, m); 1.25(22H, broad s); 1.54-1.61 (6H, m); 2.42-2.47 (2H, t); 3.93-3.99 (4H, q);4.25-4.37 (3H, m); 5.41 (1H, broad m); 5.78-5.80 (1H, d); 6.26 (1H,broad m); 7.48 (2H, broad s); 7.57-7.60 (1H, d). LC-MS (ESI) m/z (M+H)⁺:652.5.

Example 2: Synthesis of(2R,3R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-4,4-difluoro-2-(((2-oxido-4H-benzo[d][1,3,2]dioxaphosphinin-2-yl)oxy)methyl)tetrahydrofuran-3-ylnonanoate (Compound 2)

To a solution of 7 (4.5 g, 8.8 mmol) in ACN (90 mL) was added DIPEA (8.8mL, 49.6 mmol) and a solution of Int-E (3.36 g, 17.8 mmol) in DCM (20mL) dropwise at 0° C. over 15 min. The reaction mixture was stirred atroom temperature for 30 min. TBHP (5.37 mL; 5M in decane, 26.8 mmol) wasthen added dropwise at 0° C. The reaction mixture was stirred at roomtemperature for 2 h. The reaction mixture was concentrated under reducedpressure and the residue was dissolved in ethyl acetate (100 mL) andwashed with water (50 mL) and brine (50 mL). The organic layer was driedover anhydrous Na₂SO₄ and filtered. The solvent was evaporated underreduced pressure to give the crude compound which was purified by silicagel chromatography to afford 9 (1.74 g, 29%) as an off-white solid.

To a solution of 9 (1.74 g, 2.59 mmol) in DCM (34.8 mL) was added TFA(0.98 mL, 12.9 mmol) dropwise at 0° C. The reaction mixture was stirredat room temperature for 16 h. The reaction mixture was concentratedunder reduced pressure and the residue was dissolved in ethyl acetate(100 mL) and washed with saturated NaHCO₃ (50 mL). The organic layer wasdried over anhydrous Na₂SO₄ and filtered. The solvent was evaporatedunder reduced pressure to give the crude compound which was purified bysilica gel chromatography to afford the title compound (2) (0.83 g, 56%)as an off-white solid. ¹H NMR (300 MHz, d₆-DMSO): δ 0.84-0.87 (3H, t);1.25 (10H, broad s); 1.51-1.54 (2H, m); 2.37-2.41 (2H, m); 4.37-4.41(1H, m); 4.44-4.51 (2H, m); 5.37 (1H, broad s); 5.42-5.57 (2H, m);5.72-5.75 (1H, m); 6.22 (1H, broad m); 7.11-7.14 (1H, m); 7.19-7.23 (1H,m); 7.28-7.30 (1H, m); 7.35-7.47 (4H, m). LC-MS (ESI) m/z (M+H)⁺: 572.2.

Example 3: Synthesis of Compound 3

To a solution of 7 (4 g, 7.9 mmol) in DCM (80 mL) was added DIPEA (1.65mL, 9.4 mmol), DMAP (57 mg, 0.47 mmol), and a solution of Int-I (3.2 g,9.5 mmol) in DCM (20 mL) dropwise at 0° C. for 15 min. The reactionmixture was stirred at room temperature for 16 h. The reaction mixturewas concentrated under reduced pressure and the residue was dissolved inethyl acetate (100 mL) and washed with water (50 mL) and brine (50 mL).The organic layer was dried over anhydrous Na₂SO₄ and filtered. Thesolvent was evaporated under reduced pressure to afford 10 (3.0 g) as abrown liquid which was used in the next step without furtherpurification.

To a solution of 10 (3.0 g, 3.6 mmol) in DCM (30 mL) was added TFA (1.41mL, 18.45 mmol) dropwise at 0° C. The reaction mixture was stirred atroom temperature for 16 h. The solvent was evaporated under reducedpressure and the residue was diluted in ethyl acetate (100 mL) andwashed with saturated NaHCO₃ (50 mL). The organic layer was dried overNa₂SO₄ and filtered. The solvent was evaporated under reduced pressureto give crude compound which was purified by silica gel chromatographyto afford Compound 3 (0.58 g, 33%) as a colorless liquid. ¹H NMR (300MHz, d₆-DMSO): δ 0.83-0.87 (3H, m); 1.09-1.16 (18H, m); 1.25 (10H, broads); 1.53-1.60 (2H, m); 2.41-2.46 (2H, t); 4.35-4.37 (3H, broad d); 5.40(1H, broad s); 5.58-5.63 (4H, d); 5.79-5.82 (1H, d); 6.25 (1H, broad s);7.46-7.48 (2H, m); 7.57-7.59 (1H, d). LC-MS (ESI) m/z (M+H)⁺: 712.4.

Examples 4-14

The following compounds were synthesized in a similar manner asdescribed in Example 1.

Com- LC-MS Ex. pound (ESI) m/z No. No. Structure Chemical Name (M + H)⁺4 16

(2R,3R,5R)-5-(4-amino- 2-oxopyrimidin-1(2H)- (((diisopropoxyphosphoryl)oxy)methyl)-4,4- difluorotetrahydrofuran- 3-yl isobutyrate 498.4 5 17

(2R,3R,5R)-5-(4-amino- 2-oxopyrimidin-1(2H)- (((dipropoxyphosphoryl)oxy)methyl)-4,4- difluorotetrahydrofuran- 3-yl butyrate 498.4 6 18

(2R,3R,5R)-5-(4-amino- 2-oxopyrimidin-1(2H)- yl)-2-(((bis(pentyloxy)phosphoryl) oxy)methyl)-4,4- difluorotetrahydrofuran- 3-ylhexanoate 582.5 7 19

(2R,3R,5R)-5-(4-amino- 2-oxopyrimidin-1(2H)- yl)-2-(((bis(heptyloxy)phosphoryl) oxy)methyl)-4,4- difluorotetrahydrofuran- 3-yloctanoate 666.7 8 20

(2R,3R,5R)-5-(4-amino- 2-oxopyrimidin-1(2H)- yl)-2-(((bis(octyloxy)phosphoryl) oxy)methyl)-4,4- difluorotetrahydrofuran- 3-ylheptadecanoate 820.7 9 21

(2R,3R,5R)-5-(4-amino- 2-oxopyrimidin-1(2H)- yl)-2-(((bis(decyloxy)phosphoryl) oxy)methyl)-4,4- difluorotetrahydrofuran- 3-ylundecanoate 792.7 10 22

(2R,3R,5R)-5-(4-amino- 2-oxopyrimidin-1(2H)- yl)-2-(((bis(dodecyloxy)phosphoryl) oxy)methyl)-4,4- difluorotetrahydrofuran- 3-yltridecanoate 876.7 11 23

(2R,3R,5R)-5-(4-amino- 2-oxopyrimidin-1(2H)- yl)-2-(((bis(tetradecyloxy) phosphoryl)oxy)methyl)- 4,4-difluorotetrahydrofuran- 3-yl pentadecanoate 960.8 12 24

(2R,3R,5R)-5-(4-amino- 2-oxopyrimidin-1(2H)- (((bis(cyclohexyloxy)phosphoryl)oxy)methyl)- 4,4- difluorotetrahydrofuran- 3-ylcyclohexanecarboxylate 618.5 13 25

(2R,3R,5R)-5-(4-amino- 2-oxopyrimidin-1(2H)- yl)-2-(((diphenoxyphosphoryl) oxy)methyl)-4,4- difluorotetrahydrofuran- 3-ylbenzoate 600.4 14 26

(2R,3R,5R)-5-(4-amino- 2-oxopyrimidin-1(2H)- (((bis(hexyloxy)phosphoryl)oxy)methyl)- 4,4- difluorotetrahydrofuran- 3-yl nonanoate652.5

Example 15: Synthesis of(2R,3R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((((decyloxy)(hydroxy)phosphoryl)oxy)methyl)-4,4-difluorotetrahydrofuran-3-ylundecanoate (Compound 15)

To a stirred solution of tert-butylN-[1-[(2R,5R)-5-[[tert-butyl(dimethyl)silyl]oxymethyl]-3,3-difluoro-4-hydroxytetrahydrofuran-2-yl]-2-oxopyrimidin-4-yl]carbamate(5) (3.64 g, 7.6 mmol) in dry 1,4-dioxane (60 mL) was added undecanoicacid (4.71 g, 25.3 mmol), triethylamine (6.8 mL, 48.8 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.39 g,22.90 mmol) and 4-dimethylaminopyridine (91 mg, 0.7 mmol) whilemaintaining the temperature between 5-10° C. The reaction mixture wasstirred at room temperature for 2 h. The reaction mixture wasevaporated. The residue was partitioned between water (100 mL) anddichloromethane (150 mL) and the aqueous layer was extracted withdichloromethane (150 mL). The combined organic layers were washed withwater (100 mL), dried over anhydrous magnesium sulfate, filtered andevaporated. The crude product was purified by silica gel columnchromatography to give 12 (5.26 g) as a colorless oil.

To a stirred solution of 12 (5.2 g, 8.1 mmol) in distilledtetrahydrofuran (52 mL) was added triethylamine trihydrofluoride (7.6mL, 46.6 mmol) at 0° C. under argon. The reaction mixture was stirred atroom temperature for 18 h. The reaction mixture was evaporated. Theresidue was taken up in ethyl acetate (100 mL) and the organic layer waswashed with saturated aqueous sodium bicarbonate (2×50 mL), water (50mL), and brine (50 mL). The organic layer was dried over anhydrousmagnesium sulfate and evaporated. The crude product was purified bysilica gel column chromatography to give 13 (3.38 g, 83%) as a colorlessoil.

A solution of 13 (540 mg, 2.3 mmol) in freshly distilled pyridine (17mL) was stirred at 50° C. for 2 h under argon. The solution wasevaporated and the residue was taken up in freshly distilled pyridine (8mL). To the mixture was added 2,4,6-triisopropylbenzenesulfonyl chloride(1.37 g, 4.5 mmol) as a solution in freshly distilled pyridine (20 mL)and Int-J (1.20 g, 2.3 mmol) as a solution in freshly distilled pyridine(7 mL) at 40° C. under argon. The reaction mixture was stirred at 40° C.for 28 h. To the reaction mixture was added water (1.65 mL) andisopropanol (6.5 mL) and the mixture was stirred at room temperature for15 min. The mixture was evaporated. To the residue was added toluene (10mL) and the mixture was evaporated. This evaporation sequence wasrepeated 4 times. The crude product was purified by silica gelchromatography to give 14 (860 mg, 50%) as a white solid.

A suspension of 14 (1.18 g, 1.58 mmol) and hydrogen chloride (5.3 M in1,4-dioxane, 11.6 mL, 61.48 mmol) was stirred at room temperature for 29h under argon. The reaction mixture was evaporated and the residue waspurified by preparative HPLC to give the title compound (15) (260 mg,25%) as an off-white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 7.75-7.58 (m,2H), 7.43-6.95 (m, 2H), 6.24 (t, J=9.1 Hz, 1H), 5.83 (d, J=7.6 Hz, 1H),5.46-5.25 (m, 1H), 4.34-4.24 (m, 1H), 4.14-3.96 (m, 2H), 3.81-3.68 (m,2H), 2.43 (t, J=7.4 Hz, 2H), 1.61-1.44 (m, 4H), 1.32-1.16 (m, 28H),0.90-0.81 (m, 6H). LC-MS (ESI) m/z (M+H)⁺: 652.2.

Example 16 (Compound 27) was synthesized in a similar manner asdescribed in Example 15.

LC-MS Ex. Compound (ESI) m/z No. No. Structure Chemical Name (M + H)⁺ 1627

(2R,3R,5R)-5-(4-amino- 2-oxopyrimidin-1(2H)- yl)-2-((((dodecyloxy)(hydroxy) phosphoryl)oxy)methyl)- 4,4-difluorotetrahydrofuran- 3-yl tridecanoate 708.3

Examples 17-21

The following compounds (Compounds 28-32) were synthesized in a similarmanner as described in Example 2.

LC-MS Ex. Compound (ESI) m/z No. No. Structure Chemical Name (M + H)⁺ 1728

(2R,3R,5R)-5-(4- amino-2-oxopyrimidin- 1(2H)-yl)-4,4-difluoro-2-(((2-oxido-4H- benzo[d][1,3,2] dioxaphosphinin-2- yl)oxy)methyl)tetrahydrofuran-3-yl tridecanoate 628.5 18 29

(2R,3R,5R)-5-(4- amino-2-oxopyrimidin- 1(2H)-yl)-4,4-difluoro-2-(((2-oxido-4H- benzo[d][1,3,2] dioxaphosphinin-2- yl)oxy)methyl)tetrahydrofuran-3-yl pentadecanoate 654.6 19 30

(2R,3R,5R)-5-(4- amino-2-oxopyrimidin- 1(2H)-yl)-4,4-difluoro-2-(((2-oxido-4H- benzo[d][1,3,2] dioxaphosphinin-2- yl)oxy)methyl)tetrahydrofuran-3-yl heptadecanoate 682.6 20 31

(2R,3R,5R)-5-(4- amino-2-oxopyrimidin- 1(2H)-yl)-4,4-difluoro-2-(((8-methyl-2-oxido- 4H- benzo[d][1,3,2] dioxaphosphinin-2-yl)oxy)methyl) tetrahydrofuran-3-yl heptadecanoate 698.6 21 32

(2R,3R,5R)-5-(4- amino-2-oxopyrimidin- 1(2H)-yl)-4,4-difluoro-2-(((5-methyl-2-oxido- 4H- benzo[d][1,3,2] dioxaphosphinin-2-yl)oxy)methyl) tetrahydrofuran-3-yl heptadecanoate 698.6

Examples 22-25

The following compounds (Compounds 33-36) were synthesized in a similarmanner as described in Example 3.

Ex. Compound LC-MS (ESI) No. No. Structure m/z (M + H)⁺ 22 33

768.6 23 34

796.7 24 35

824.8 25 36

852.8

Example 26: Synthesis of Isomers1-[(4aR,6R,7aR)-7,7-difluoro-2-octoxy-2-oxo-4,4a,6,7a-tetrahydrofuro[3,2-d][1,3,2]dioxaphosphinin-6-yl]-4-amino-pyrimidin-2-one(Compound 41A) and (Compound 41B)

4-amino-1-[(2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]pyrimidin-2-one(20 g, 75.99 mmol, 1 eq.) was dissolved in pyridine (500 mL) and themixture was cooled down to 0° C. TMSCl (49.53 g, 455.93 mmol, 6 eq.) wasadded and the mixture was stirred at 25° C. for 12 h. DMAP (9.28 g,75.99 mmol, 1 eq.) and MMTrCl (46.93 g, 151.98 mmol, 2 eq.) were addedand the reaction mixture was stirred at 50° C. for 16 h. The reactionmixture was quenched with cold sat.aq.NaHCO₃ slowly and extracted withEtOAc (500 mL×3). The organic layer was washed with brine (200 ml),dried over Na₂SO₄ and concentrated in vacuum. The crude product wascombined with toluene (100 mL) and then concentrated again to yield1-[(2R,4R,5R)-3,3-difluoro-4-trimethylsilyloxy-5-(trimethylsilyloxymethyl)tetrahydrofuran-2-yl]-4-[[(4-methoxyphenyl)-diphenyl-methyl]amino]pyrimidin-2-one(38) (103 g, crude, two parallel batches) as a yellow oil, which wasused into the next step without further purification.

To a solution of1-[(2R,4R,5R)-3,3-difluoro-4-trimethylsilyloxy-5-(trimethylsilyloxymethyl)tetrahydrofuran-2-yl]-4-[[(4-methoxyphenyl)-diphenyl-methyl]amino]pyrimidin-2-one(38) (103 g, 151.49 mmol, 1 eq.) in MeOH (1 L) was added NH₄F (28.05 g,757.47 mmol, 5 eq.). The reaction mixture was stirred at 70° C. for 1 hrand then concentrated in vacuum. The residue was purified by columnchromatography to yield1-[(2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-4-[[(4-methoxyphenyl)-diphenylmethyl]amino]pyrimidin-2-one(39) (56 g, 69%) as a white solid. ¹H-NMR (400 MHz, CDCl₃) δ 7.26-7.21(m, 8H), 7.19-7.12 (m, 4H), 7.10-7.12 (m, 2H), 7.02-6.75 (m, 2H), 6.01(s, 1H), 5.07 (m, 1H), 4.38-4.36 (m, 1H), 3.86-3.81 (m, 2H), 3.72 (s,3H).

To a mixture of1-[(2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-4-[[(4-methoxyphenyl)-diphenyl-methyl]amino]pyrimidin-2-one(39) (14.5 g, 27.08 mmol, 1 eq.) in DCM (300 mL) was added Et₃N (19.18g, 189.53 mmol, 7 eq.). The reaction was cooled to −20° C., and then1-dichlorophosphoryloxyoctane (Int-K) (13.38 g, 54.15 mmol, 2 eq.) wasadded dropwise over 10 min. The mixture was stirred at −20° C. for 0.5h, and then 1-methylimidazole (8.89 g, 108.30 mmol, 4 eq.) was addeddropwise over 15 min. The mixture was stirred at −15° C. for 1 h andthen slowly warmed to 25° C. and stirred for 12 h. The mixture wasconcentrated and the residue was purified by column chromatography toyield1-[(4aR,6R,7aR)-7,7-difluoro-2-octoxy-2-oxo-4,4a,6,7a-tetrahydrofuro[3,2-d][1,3,2]dioxaphosphinin-6-yl]-4-[[(4-methoxyphenyl)-diphenyl-methyl]amino]pyrimidin-2-one(40) (7.8 g, 41%) as a white solid. ¹H-NMR (400 MHz, CDCl₃) δ 7.33-7.25(m, 10H), 7.20-7.18 (m, 2H), 7.12-7.10 (m, 1H), 6.84-6.82 (m, 3H),5.12-5.09 (m, 1H), 4.60-4.57 (m, 2H), 4.18-4.10 (m, 4H), 3.80 (s, 3H),1.77-1.68 (m, 2H), 1.26-1.23 (m, 10H), 0.88-0.84 (m, 3H).

To a solution of1-[(4aR,6R,7aR)-7,7-difluoro-2-octoxy-2-oxo-4,4a,6,7a-tetrahydrofuro[3,2-d][1,3,2]dioxaphosphinin-6-yl]-4-[[(4-methoxyphenyl)-diphenyl-methyl]amino]pyrimidin-2-one(40) (7.8 g, 10.99 mmol, 1 eq.) in water (20 mL) was added HCOOH (80 mL)and the mixture was stirred at 25° C. for 12 hrs. The mixture wasconcentrated in vacuum and the residue was purified by prep-HPLC toyield two stereoisomers (two stereoisomers at phosphorous) of1-[(4aR,6R,7aR)-7,7-difluoro-2-octoxy-2-oxo-4,4a,6,7a-tetrahydrofuro[3,2-d][1,3,2]dioxaphosphinin-6-yl]-4-aminopyrimidin-2-one:major isomer (41A) (1.91 g, 39%) and minor isomer (41B) (1.55 g, 31%) aswhite solids. The stereochemistry at phosphorous was not assigned forCompounds 41A and 41B. Major isomer (41A): ¹H-NMR (400 MHz, DMSO) δ 7.80(s, 1H), 7.52 (d, 2H, J=11.6 Hz), 6.45 (s, 1H), 5.81 (d, 1H, J=7.6 Hz),4.95 (s, 1H), 4.75-4.71 (m, 2H), 4.28 (s, 1H), 4.15-4.09 (s, 2H),1.76-1.66 (m, 2H), 1.37-1.35 (m, 2H), 1.27-1.26 (m, 8H), 0.87-0.84 (m,3H). QC (ESI+): 438.16 (M+H). Minor isomer (41B): ¹H-NMR (400 MHz, DMSO)δ 7.80 (s, 1H), 7.53 (d, 2H, J=6.8 Hz), 6.45 (s, 1H), 5.80 (d, 1H, J=8.0Hz), 5.30 (s, 1H), 4.76-4.64 (m, 2H), 4.38 (s, 1H), 4.13-4.08 (s, 2H),1.65-1.60 (m, 2H), 1.32-1.26 (m, 10H), 0.88-0.85 (m, 3H). QC (ESI+):438.16 (M+H).

Examples 27-31

The following compounds (Compounds 42A, 42B, 43A, 43B, 44A, 44B, 45A,45B, 46A, and 46B) were synthesized in a similar manner as described inExample 26. As in Example 26, the stereochemistry at phosphorous was notassigned for the compounds of Examples 27-31.

LC-MS Ex. Compd. (ESI) m/z No. No. Structure Chemical Name (M + H)⁺ 2742A (isomer 1)

4-amino-1- ((4aR,6R,7aR)-2- (decyloxy)-7,7-difluoro-2-oxidotetrahydro-4H- furo[3,2-d] [1,3,2]dioxaphosphinin-6-yl)pyrimidin-2(1H)- one 466.2 42B (isomer 2)

4-amino-1- ((4aR,6R,7aR)-2- (decyloxy)-7,7-difluoro-2-oxidotetrahydro-4H- furo[3,2-d] [1,3,2]dioxaphosphinin-6-yl)pyrimidin-2(1H)- one 466.2 28 43A (isomer 1)

4-amino-1- ((4aR,6R,7aR)-7,7- difluoro-2- (hexadecyloxy)-2-oxidotetrahydro-4H- furo[3,2-d] 550.3 [1,3,2]dioxaphosphinin-6-yl)pyrimidin-2(1H)- one 43b (isomer 2)

4-amino-1- ((4aR,6R,7aR)-7,7- difluoro-2- (hexadecyloxy)-2-oxidotetrahydro-4H- furo[3,2-d] 550.3 [1,3,2]dioxaphosphinin-6-yl)pyrimidin-2(1H)- one 29 44A (isomer 1)

4-amino-1- ((4aR,6R,7aR)-7,7- difluoro-2- (octadecyloxy)-2-oxidotetrahydro-4H- furo[3,2-d] 578.3 [1,3,2]dioxaphosphinin-6-yl)pyrimidin-2(1H)- one 44B (isomer 2)

4-amino-1- ((4aR,6R,7aR)-7,7- difluoro-2- (octadecyloxy)-2-oxidotetrahydro-4H- furo[3,2-d] 578.3 [1,3,2]dioxaphosphinin-6-yl)pyrimidin-2(1H)- one 30 45A (isomer 1)

4-amino-1- ((4aR,6R,7aR)-7,7- difluoro-2-(icosyloxy)-2-oxidotetrahydro-4H- furo[3,2-d] [1,3,2]dioxaphosphinin- 606.36-yl)pyrimidin-2(1H)- one 45B (isomer 2)

4-amino-1- ((4aR,6R,7aR)-7,7- difluoro-2-(icosyloxy)-2-oxidotetrahydro-4H- furo[3,2-d] [1,3,2]dioxaphosphinin- 606.36-yl)pyrimidin-2(1H)- one 31 46A (isomer 1)

4-amino-1- ((4aR,6R,7aR)-2- (docosyloxy)-7,7- difluoro-2-oxidotetrahydro-4H- furo[3,2-d] 634.4 [1,3,2]dioxaphosphinin-6-yl)pyrimidin-2(1H)- one 46B (isomer 2)

4-amino-1- ((4aR,6R,7aR)-2- (docosyloxy)-7,7- difluoro-2-oxidotetrahydro-4H- furo[3,2-d] 634.4 [1,3,2]dioxaphosphinin-6-yl)pyrimidin-2(1H)- one

Examples 32-35

The following compounds are synthesized in a similar manner as describedin Example 3.

Ex. No. Structure 32

33

34

35

Cellular Pharmacology

Compounds are tested for their ability to impair cancer cellproliferation and/or induce cell death. For cellular proliferationstudies, cultured cells are treated with the test compound for 24-120hours. After compound treatment, cell proliferation is assessed by usingmethods including, but not limited to, Cell-Titer-Glo® (Promega), AlamarBlue, LIVE/DEAD® (ThermoFisher), BrdU incorporation, and live-cellimaging.

The cancer lines used include, but are not limited to, PANC-1,MiaPaCa-2, BxPC-3 (pancreatic cancer), RT112 (bladder cancer), MCF-7(breast cancer), and A549 (non-small cell lung cancer). GemcitabineHydrochloride serves as a control for activity.

Protocol for the Cellular Proliferation Assay in BxPC-3 Cells

BxPC-3 (pancreatic adenocarcinoma) cell line was purchased from theAmerican Type Culture Collection (Catalog #CRL-1687) and grown inRPMI-1640 medium (e.g. Corning #10-040-CV) with 10% Heat InactivatedFetal Calf Serum at 37° C. and 5% CO2 (as recommended by the ATCC).

Cultures were grown in 175 mm² plates to 80% confluence, and cells weretrypsinized to a single-cell suspension. Cells were then resuspended ingrowth medium to a density of 25,00 cells/ml. They were then plated into96-well assay plates (Corning #3917) in a volume of 100 ul/well (2,500cells/well). Cells were allowed to adhere to plates for 24 h at 37° C.and 5% CO₂). Compounds were then added to the wells using an 11-foldserial dilution scheme (over 9 dilutions, generally ranging from 30μM-30 pM), and the cells were incubated for an additional 120 hours.After 120 h, 90 ul of Cell-Titer Glo reagent (Promega #G7572) was added,and the plates were read using a luminescence counter (e.g., BioTekSynergy HTX at 100 ms read time).

Potency determination were performed by 4-parameter fit of the dose vs.luminescence data using XLFit software (IDBS) with a one site doseresponse model (Model 205; fit=(A+((B−A)/(1+((C/x){circumflex over( )}D)))). The EC₅₀ was generally expressed as the inflection point (Cparameter) for the fit when the upper and lower portions of the responsecurve were well-defined. In cases where full inhibition of cell growthwas not observed at the highest concentration used, EC₅₀ was reported asthe concentration that resulted in 50% loss of Cell-Titer-Glo signal(compared to untreated control).

Potency of compounds in BxPC-3 cells is shown in Table 1:

TABLE 1 Compound EC₅₀ Gemcitabine Hydrochloride +++  1 +++  2 ++++  3++++ 16 ++ 17 + 18 ++ 19 ++ 20 + 21 + 22 + 23 + 24 + 25 + 28 ++++ 29++++ 30 ++++ 31 ++++ 32 ++++ 33 ++++ 34 ++++ 35 ++++ 36 ++++ 42A ++++43A +++ 44A +++ 45A ++ 46A + ++++ = EC₅₀ < 1 nM; +++ = 1 nM ≤ EC₅₀ < 100nM; ++ = nM ≤ EC₅₀ < 1 μM; + = 1 μM ≤ EC₅₀ < 25 μMAnimal Pharmacology

Compounds are tested to impair tumor growth in rodents using several“xenograft” model systems. Initially, immune-deficient (e.g. SCID) miceare implanted subcutaneously with tumor cells (using either tumor celllines or human patient-derived tumor tissue) until tumors are palpable(˜100-200 mm³). Test article is administered intravenously at varyingdoses and schedules, and anti-tumor effect is determined by physicalmeasurement of tumors using standard methods (i.e., calipermeasurements). Additional measures of anti-tumor effect include time ofsurvival, gain/loss of body weight, non-invasive visualization of tumormass (i.e., ultrasound, positron emission tomography, optical imaging),or direct visualization of tumor growth/metastasis by necropsy.

In addition to the aforementioned xenograft models, a variety ofgenetically-engineered mouse models (GEMINI) of cancer are employed. Inthese models, GEMM mice are allowed to spontaneously grow tumors, atwhich time test article administration is initiated. Determination ofanti-tumor effect is implemented by caliper measurement of lesions, timeof survival, gain/loss of body weight, non-invasive visualization oftumor mass (i.e., ultrasound, positron emission tomography, opticalimaging), or direct visualization of tumor growth/metastasis bynecropsy.

In both types of models, gemcitabine hydrochloride is used as acomparator. Additionally, other common anti-neoplastic compounds (e.g.,paclitaxel, 5-fluorouracil, erlotinib etc.) are used as controlcompounds depending on the tumor type being studied.

Additional Measurements

In addition to the functional assays described above, a series of cell-and animal-based experiments are performed to determine the uptake(i.e., in tumor vs. normal tissue) and catabolism/metabolism of testcompounds. For instance, test compounds are applied to cells growing inculture for varying amounts of time. Subsequently, cells (and media) arecollected and analyzed to determine the concentration of parent compoundand metabolites.

For example, compounds were evaluated for the liberation of gemcitabinein both human liver microsomes and human hepatocytes.

Protocol for metabolic stability in human liver microsomes:

[Compound]=1 μM

[LM]=0.5 mg/mL

[NADPH]=0 or 1 mM

Buffer=100 mM Potassium Phosphate, pH 7.4

Time=0, 15, 30, and 60 min

Temperature=37° C.

Liver microsomes tissue fractions were used for in vitro assessment ofmetabolic stability of various compounds by cytochrome P450 (CYP450)mediated phase I oxidation, and metabolism through other pathways. Humanliver microsomes tissue fractions were obtained from Corning Gentest.

The assay is carried out in 96-well microtiter plates. Compounds wereincubated at 37° C. in the presence of human liver microsomes. Reactionmixtures (25 μL) contain a final concentration of 1 μM test compound,0.5 mg/mL liver microsomes protein, and 1 mM NADPH in 100 mM potassiumphosphate, pH 7.4 buffer. At each of the time points (0, 15, 30, and 60minutes), 150 μL of quench solution (100% acetonitrile with 0.1% formicacid) with internal standard bucetin was transferred to each well.Verapamil was included as a positive control to verify assayperformance. The extent of metabolism is determined as the formation ofthe drug gemcitabine. Plates were sealed and centrifuged at 4° C. for 15minutes at 4000 rpm. The supernatant was transferred to fresh plates forLC/MS/MS analysis.

All samples were analyzed on LC/MS/MS using an AB Sciex API 4000instrument, coupled to a Shimadzu LC-20AD LC Pump system. Analyticalsamples were separated using a Waters Atlantis T3 dC18 reverse phaseHPLC column (50 mm×2.1 mm, 3 um) at a flow rate of 0.3 mL/min. Themobile phase consisted of 0.1% formic acid in water (solvent A) and 0.1%formic acid in 100% acetonitrile (solvent B).

Results:

Relative Peak Area Ratio (gemcitabine/internal standard) Compound 0 min15 min 30 min 60 min  1  7.7 15.1 12.7 18.1  2 10.0 17.8 17.4 47.5  3 0.0  0.0  0.0  8.3 21  0.0  0.0  0.0  1.9 24  0.0  0.0  0.0  0.0 28 0.0 14.8 18.7 58.1 30  0.0  4.9  8.2 25.5 31  0.0  1.6  6.5 23.7 33 0.0 21.1 19.7 26.0 35  0.0  0.0  1.6  6.3 42A  0.0  0.0  4.2  7.4 43A 0.0  0.0  0.0  9.7

Protocol for metabolic stability in human hepatocytes:

[Compound]=1

[Hepatocytes]=0.5 million cells/mL

Time=0, 60, 120, and 180 min

Temperature=37° C.

Metabolic stability of testing compound was evaluated using humanhepatocytes to determine the formation of gemcitabine. Human LiverPool™20-donor cryopreserved hepatocytes are obtained from BioIVT.

Cryopreserved hepatocytes were removed from the liquid nitrogen tank andthawed in a 37° C. water bath. As soon as the cells pull away from thevial wall, they were decanted into 48 mL of warm HT medium. Cells werecentrifuged for four minutes at 420 rpm (50 g). After removing thesupernatant, pellet was re-suspended in warm DMEM medium. Cell densitywas counted by a hemacytometer.

The assay was carried out in 96-well microtiter plates. Compounds wereincubated for 0, 60, 120, and 180 minutes at 37° C. with hepatocytes.Reaction mixtures (50 μL) contained a final concentration of 1 testcompound, 0.5 million cells/mL hepatocytes in the DMEM medium. At eachof the time points (0, 1, 2, and 3 hours), 150 μL of quench solution(100% acetonitrile with 0.1% formic acid) with internal standard bucetinwas transferred to each well. Midazolam was included as a positivecontrol to verify assay performance. The extent of metabolism wasdetermined as the formation of the drug gemcitabine. Plates were sealedand centrifuged at 4° C. for 15 minutes at 4000 rpm. The supernatant wastransferred to fresh plates for LC/MS/MS analysis.

All samples were analyzed on LC/MS/MS using an AB Sciex API 4000instrument, coupled to a Shimadzu LC-20AD LC Pump system. Analyticalsamples were separated using a Waters Atlantis T3 dC18 reverse phaseHPLC column (50 mm×2.1 mm, 3 um) at a flow rate of 0.3 mL/min. Themobile phase consisted of 0.1% formic acid in water (solvent A) and 0.1%formic acid in 100% acetonitrile (solvent B).

Relative Peak Area Ratio (gemcitabine/internal standard) Compound 0 min15 min 30 min 60 min  1 0.0  0.0  0.0  2.4  2 0.0 55.6 58.8 49.2  3 0.054.7 55.8 47.1 21 0.0  0.0  0.0  0.0 24 0.0  0.0  0.0  0.0 28 0.0 41.454.8 42.3 30 0.0  0.0  0.0  6.4 31 0.0  0.0  7.5  6.3 33 0.0 18.3 24.223.8 35 0.0  0.0  0.0  0.0 42A 0.0  0.0  3.7  8.6 43A 0.0  0.0  0.0  0.0

Other experiments are performed in tumor-bearing animals to determinethe distribution of test article as well as active (and inactive)metabolites in blood, normal tissue, and tumor.

What is claimed is:
 1. A compound having the structure of Formula (II):

wherein: R³ is H, —C(O)R⁹, or —C(O)OR⁹; R⁴ is H; R⁹ is C₁₋₈alkyl; R¹¹ isC₆₋₂₂alkyl, C₃₋₂₂alkenyl, C₃₋₂₂alkynyl, C₃₋₂₂haloalkyl,—C₁₋₄alkyl-OC(O)C₁₋₈alkyl, C₆₋₁₀aryl, —C₁₋₈alkyl-C₆₋₁₀aryl,C₂₋₉heteroaryl, or —C₁₋₈alkyl-C₂₋₉heteroaryl, wherein C₆₋₁₀aryl,—C₁₋₈alkyl-C₆₋₁₀aryl, C₂₋₉heteroaryl, or —C₁₋₈alkyl-C₂₋₉heteroaryl areoptionally substituted with 1, 2, 3, or 4 R¹²; each R¹² is independentlyselected from halogen, C₁₋₈alkyl, C₁₋₈haloalkyl, C₁₋₈alkoxy, and—C(O)R¹³; and each R¹³ is independently selected from C₁₋₁₂alkyl; or apharmaceutically acceptable salt thereof.
 2. The compound of claim 1, ora pharmaceutically acceptable salt thereof, wherein R¹¹ is C₆₋₂₂alkyl.3. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R¹¹ is C₁₆₋₂₂alkyl.
 4. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R¹¹ is—C₁₋₄alkyl-OC(O)C₁₋₈alkyl.
 5. The compound of claim 4, or apharmaceutically acceptable salt thereof, wherein R¹¹ is —C₁₋₂alkyl-OC(O)C₁₋₆alkyl.
 6. The compound of claim 5, or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is —CH₂—OC(O)C(CH₃)₃.
 7. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R¹¹ is phenyl optionally substituted with 1, 2, or 3 R¹².
 8. Thecompound of claim 7, or a pharmaceutically acceptable salt thereof,wherein R¹¹ is phenyl optionally substituted with 1, 2, or 3 R¹², andeach R¹² is independently selected from C₁₋₈alkyl, C₁₋₈alkoxy, and—C(O)R¹³.
 9. The compound of claim 8, or a pharmaceutically acceptablesalt thereof, wherein R¹¹ is phenyl optionally substituted with 1 or 2R¹², and each R¹² is independently selected from C₁₋₈alkyl andC₁₋₈alkoxy.
 10. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is —C₁₋₈alkyl-C₆₋₁₀aryl optionallysubstituted with 1, 2, 3, or 4 R¹².
 11. The compound of claim 10, or apharmaceutically acceptable salt thereof, wherein R¹¹ is —CH₂-phenyloptionally substituted with 1, 2, or 3 R¹².
 12. The compound of claim11, or a pharmaceutically acceptable salt thereof, wherein R¹¹ is—CH₂-phenyl optionally substituted with 1, 2, or 3 R¹², and each R¹² isindependently selected from C₁₋₈alkyl, C₁₋₈alkoxy, and —C(O)R¹³.
 13. Thecompound of claim 12, or a pharmaceutically acceptable salt thereof,wherein R¹¹ is —CH₂-phenyl optionally substituted with 1 or 2 R¹², andeach R¹² is independently selected from C₁₋₈alkyl and C₁₋₈alkoxy. 14.The compound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R³ is H.
 15. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R³ is —C(O)R⁹.
 16. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein R³ is—C(O)OR⁹.
 17. The compound of claim 1 selected from:

or a pharmaceutically acceptable salt thereof.
 18. A pharmaceuticalcomposition comprising a compound of claim 1, or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptableexcipient.
 19. A method of treating cancer in a patient in need thereof,comprising administering to the patient a therapeutically effectiveamount of a compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein the cancer is selected from pancreatic cancer, bladdercancer, breast cancer, and non-small cell lung cancer.